Isothiazoloanthrones, isoxazoloanthrones, isoindolanthrones and derivatives thereof a JNK inhibitors and compositions and methods related thereto

ABSTRACT

Isaothiazoloanthrones, isooxazoloanthrones, isoindolanthrones, and derivatives thereof having the general formula: 
     
       
         
         
             
             
         
       
         
         
           
             and pharmaceutically acceptable salts thereof, wherein R 0  is —CH 2 —, —SO—, —O—, —SO 2 —, or —S—; compositions comprising the iazoloanthrones, isooxazoloanthrones, isoindolanthrones, and derivatives thereof; and methods for treating or preventing a disorder alleviated by inhibiting Jun N-terminal kinase (JNK) by administering the isaothiazoloanthrones, isooxazoloanthrones, isoindolanthrones, and derivatives thereof are described herein.

This application is a Divisional of U.S. patent application Ser. No.10/071,390 filed Feb. 7, 2002 now U.S. Pat. No. 6,987,184, which claimsbenefit of U.S. Provisional Application No. 60/269,013, filed Feb. 15,2001, each Application being incorporated by reference herein in itsentirety.

1. FIELD OF THE INVENTION

This invention is generally directed to isothiazoloanthrones,isoxazoloanthrones, isoindoianthrones, and derivatives thereof;compositions comprising the isothiazoloanthrones, isoxazoloanthrones,isoindolanthrones, and derivatives thereof; and methods for treating orpreventing a disease or disorder alleviated by inhibiting Jun N-terminalkinase, (JNK) comprising administering an effective amount of theisothiazoloanthrones, isoxazoloanthrones, isoindolanthrones, orderivatives thereof to a patient in need thereof

2. BACKGROUND OF THE INVENTION

The Jun N-terminal kinase (JNK) pathway is activated by exposure ofcells to environmental stress or by treatment of cells withpro-inflammatory cytokines. Targets of the JNK pathway include thetranscription factors c-jun and ATF2 (Whitmarsh A. J., and Davis R. J.J. Mol. Med. 74:589-607, 1996). These transcription factors are membersof the basic leucine zipper (bZIP) group that bind as homo- andhetero-dimeric complexes to AP1 and AP-1-like sites in the promoters ofmany genes (Karin M., Liu Z. G. and Zandi E. Curr Opin Cell Biol9:240-246, 1997). JNK binds to the N-terminal region of c-jun and ATF-2and phosphorylates two sites within the activation domain of eachtranscription factor (Hibi M., Lin A., Smeal T., Minden k, Karin M.Genes Dev. 7:2135-2148, 1993; Mohit A. A., Martin M. H., and Miller C.A. Neuron 14:67-75, 199). Three JNK enzymes have been identified asproducts of distinct genes (Hibi et al, supra; Mohit et al., supra). Tendifferent isoforms of JNK have been identified. These representalternatively spliced forms of three different genes: JNK1, JNK2, andJNK3. JNK1 and 2 are ubiquitously expressed in human tissues, whereasJNK3 is selectively expressed in the brain, heart, and testis (Dong, C.,Yang, D., Wysk, M., Whitmarsh, A., Davis, R., Flavell, R. Science270:1-4, 1998). Gene transcripts are alternatively spliced to producefour-JNK1 isoforms, four-JNK2 isoforms, and two-JNK3 isoforms. JNK1 and2 are expressed widely in mammalian tissues, whereas JNK3 is expressedalmost exclusively in the brain. Selectivity of JNK signaling isachieved via specific interactions of JNK pathway components and by useof scaffold proteins that selectively bind multiple components of thesignaling cascade. JIP-1 (JNK-interacting protein-1) selectively bindsthe MAPK module, MLK→JNKK1→JNK. It has no binding affinity for a varietyof other MAPK cascade enzymes. Different scaffold proteins are likely toexist for other MAPK signaling cascades to preserve substratespecificity.

JNKs are activated by dual phosphorylation on Thr-183 and Tyr-185. JNKK1(also known as MKK 4) and JNKK2 (MKK7), two MAPKK level enzymes, canmediate JNK activation in cells (Lin A., Minden A., Martinetto H.,Claret F.-Z., Lange-Carter C., Mercurio F., Johnson G. L., and Karin M.Science 268:286-289, 1995; Tournier C., Whitmarsh A. J., Cavanagh J.,Barrett T., and Davis R. J. Proc. Nat. Acad. Sci. USA 94:7337-7342,1997). JNKK2 specifically phosphorylates JNK, whereas JNKK1 can alsophosphorylate and activate p38. Both JNKK1 and JNKK2 are widelyexpressed in mammalian tissues. JNKK1 and JNKK2 are activated by theMAPKKK enzymes, MEKK1 and 2 (Lange-Carter C. A., Pleiman C. M., GardnerA. M., Blumer K. J., and Johnson G. L., Science, 260:315-319, 1993; YanM., Dai J. C., Deak J. C., Kyrakis J. M., Zon L. I., Woodgett J. R., andTempleton D. J., Nature, 372:798-781, 1994). Both MEKK1 and MEKK2 arewidely expressed in mammalian tissues.

Activation of the JNK pathway has been documented in a number of diseasesettings, providing the rationale for targeting this pathway for drugdiscovery. In addition, molecular genetic approaches have validated thepathogenic role of this pathway in several diseases. For example,autoimmune and inflammatory diseases arise from the over-activation ofthe immune system. Activated immune cells express many genes encodinginflammatory molecules, including cytokines, growth factors, cellsurface receptors, cell adhesion molecules, and degradative enzymes.Many of these genes are regulated by the JNK pathway, through activationof the transcription factors AP-1 and ATF-2, including TNFa, IL-2,E-selectin, and matrix metalloproteinases such as collagenase-1 (ManningA. M. and Mercurio F., Exp Opin Invest Drugs, 6: 555-567, 1997).Monocytes, tissue macrophages, and tissue mast cells are key sources ofTNFa production. The JNK pathway regulates TNFa production in bacteriallipopolysaccharide-stimulated macrophages, and in mast cells stimulatedthrough the FceRII receptor (Swantek J. L., Cobb M. H., Geppert T. D.,Mol. Cell. Biol., 17:6274-6282, 1997; Ishizuka, T., Tereda N., Gerwins,P., Hamelmann E., Oshiba A., Fanger G. R., Johnson G. L., and GelfiandE. W., Proc. Nat. Acad. Sci. USA, 94:6358-6363, 1997). Inhibition of JNKactivation effectively modulates TNFa secretion from these cells. TheJNK pathway therefore regulates production of this key pro-inflammatorycytokine. Matrix metalloproteinases (MMPs) promote cartilage and boneerosion in rheumatoid arthritis, and generalized tissue destruction inother autoimmune diseases. Inducible expression of MMPs, including MMP-3and MMP-9, type II and IV collagenases, are regulated via activation ofthe JNK pathway and AP-1 (Gum, R., Wang, H., Lengyel, E., Juarez, J.,and Boyd, D., Oncogene, 14:1481-1493, 1997). In human rheumatoidsynoviocytes activated with TNFa, IL-1, or Fas ligand the JNK pathway isactivated (Han Z., Boyle D. L., Aupperle K. R., Bennett B., Manning A.M., Firestein G. S., J. Pharm. Exp. Therap., 291:1-7, 1999; Okamoto K.,Fujisawa K., Hasunuma T., Kobata T., Sumida T., and Nishioka K., Arth &Rheum, 40: 919, 1997). Inhibition of JNK activation results in decreasedAP-1 activation and collagenase-1 expression (Han et al., supra). TheJNK pathway therefore regulates MMP expression in cells involved inrheumatoid arthritis.

Inappropriate activation of T lymphocytes initiates and perpetuates manyautoimmune diseases, including asthma, inflammatory bowel disease, andmultiple sclerosis. The JNK pathway is activated in T cells by antigenstimulation and CD28 receptor co-stimulation and regulates production ofthe growth factor IL-2 and cellular proliferation (Su B., Jacinto E.,Hibi M., Kallunki T., Karin M., Ben-Neriah Y. Cell, 77:727-736, 1994;Faris M., Kokot N., Lee L., and Nel A. E., J. Biol. Chem.,271:27366-27373, 1996). Peripheral T cells from mice geneticallydeficient in JNKK1 show decreased proliferation and IL-2 productionafter CD28 co-stimulation and PMA/Ca2+ ionophore activation, providingimportant validation for the role of the JNK pathway in these cells(Nishina H., Bachmann M., Oliveria-dos-Santos A. J., et al., J. Exp.Med., 186: 941-953, 1997). It is known that T cells activated by antigenreceptor stimulation in the absence of accessory cell-derivedco-stimulatory signals lose the capacity to synthesize IL-2, a statecalled clonal anergy. This is an important process by whichauto-reactive T cell populations are eliminated from the peripheralcirculation. Of note, anergic T cells fail to activate the JNK pathwayin response to CD3- and CD28-receptor co-stimulation, even thoughexpression of the JNK enzymes is unchanged (Li W., Whaley C. D., MondinoA., and Mueller D. L., Science 271:1272-1276, 1996). Recently, theexamination of JNK-deficient mice revealed that the JNK pathway plays akey role in T cell activation and differentiation to T helper 1 and 2cell types. JNK 1 or JNK2 knockout mice develop normally and arephenotypically unremarkable. Activated naive CD4+ T cells from thesemice fail to produce IL-2 and do not proliferate well (Sabapathy, K, Hu,Y, Kallunki, T, Schreiber, M, David, J-P, Jochum, W, Wagner, E, Karin,M,. Curr Biol 9:116-125, 1999). It is possible to induce T celldifferentiation in T cells from these mice, generating Th1 cells(producers of IFN-g and TNFβ) and Th2 effector cells (producers of IL-4,IL-5, IL-6, IL-10, and IL-13). Deletion of either JNK1 or JNK2 in miceresulted in a selective defect in the ability of Th1 effector cells toexpress IFNg. This suggests that JNK1 and JNK2 do not have redundantfunctions in T cells and that they play different roles in the controlof cell growth, differentiation, and death. The JNK pathway therefore,is an important point for regulation of T cell responses to antigen.

Cardiovascular disease (CVD) accounts for nearly one quarter of totalannual deaths worldwide. Vascular disorders such as atherosclerosis andrestenosis result from dysregulated growth of the vessel wall,restricting blood flow to vital organs. The JNK pathway is activated byatherogenic stimuli and regulates local cytokine and growth factorproduction in vascular cells (Yang, D D, Conze, D, Whitmarsh, A J, etal., Immunity, 9:575, 1998). In addition, alterations in blood flow,hemodynamic forces, and blood volume lead to JNK activation in vascularendothelium, leading to AP-1 activation and pro-atherosclerotic geneexpression (Aspenstrom P., Lindberg U., and Hall A., Curr. Biol.6:70-77, 1996). Ischemia and ischemia coupled with reperfusion in theheart, kidney, or brain results in cell death and scar formation, whichcan ultimately lead to congestive heart failure, renal failure, orcerebral dysfunction. In organ transplantation, reperfusion ofpreviously ischemic donor organs results in acute leukocyte-mediatedtissue injury and delay of graft function. The JNK pathway is activatedby ischemia and reperfusion (Li Y., Shyy J., Li S., Lee J., Su B., KarinM., Chien S., Mol. Cell. Biol., 16:5947-5954, 1996), leading to theactivation of JNK-responsive genes and leukocyte-mediated tissue damage.In a number of different settings JNK activation can be either pro- oranti-apoptotic. JNK activation is correlated with enhanced apoptosis incardiac tissues following ischemia and reperfusion (Pombo C M, BonventreJ V, Avruch J, Woodgett J R, Kyriakis J. M, Force T., J. Biol. Chem.269:26546-26551, 1994).

Cancer is characterized by uncontrolled growth, proliferation andmigration of cells. Cancer is the second leading cause of death with500,000 deaths and an estimated 1.3 million new cases in the UnitedStates in 1996. The role of signal transduction pathways contributing tocell transformation and cancer is a generally accepted concept. The JNKpathway leading to AP-1 appears to play a critical role in cancer.Expression of c-jun is altered in early lung cancer and may mediategrowth factor signaling in non-small cell lung cancer (Yin T., SandhuG., Wolfgang C. D., Burrier A., Webb R. L., Rigel D. F. Hai T., andWhelan J., J. Biol. Chem. 272:19943-19950, 1997). Indeed,over-expression of c-jun in cells results in transformation, andblocking c-jun activity inhibits MCF-7 colony formation (Szabo E., RiffeM., Steinberg S. M., Birrer M. J., Linnnoila R. I., Cancer Res.56:305-315, 1996). DNA-damaging agents, ionizing radiation, and tumornecrosis factor activate the JNK pathway. In addition to regulatingc-jun production and activity, JNK activation can regulatephosphorylation of p53 and, thus, can modulate cell cycle progression(Chen T. K., Smith L. M., Gebhardt D. K., Birrer M. J., Brown P. H.,Mol. Carcinogenesis, 15:215-226, 1996). The oncogene BCR-Abl, associatedwith t(9,22) Philadelphia chromosome translocation of chronicmyelogenous leukemia, activates JNK and leads to transformation ofhematopoietic cells (Milne D. M., Campbell L. E., Campbell D. G., MeekD. W., J. Biol. Chem. 270:5511-5518, 1995). Selective inhibition of JNKactivation by a naturally occurring JNK inhibitory protein, calledJIP-1, blocks cellular transformation caused by BCR-Abl expression(Raitano A. B., Halpern J. R., Hambuch T. M., Sawyers C. L., Proc. Nat.Acad. Sci USA, 92:11746-11750, 1995). Thus, JNK inhibitors may blocktransformation and tumor cell growth.

Stroke is the 3^(rd) leading cause of death and a leading cause ofdisability in the U.S. Stroke, along with neurodegenerative diseases,such as Alzheimer's (AD) and Parkinson's disease (PD) impose a hugeburden on the health care industry by impacting the quality of life ofthose affected. Loss of neuronal cell populations in stroke, AD, or PDunderlies the motor and/or cognitive deficiencies in these patientpopulations. The mechanism by which neurons die in response to insulthas not been fully elucidated; however, activation of the JNK pathwayhas been implicated as a major signaling pathway for neuronal apoptosis.(For review see Mielke K. and Herdegen T. Prog. Neurobiol. 61:45-60,2000). A variety of insults have been shown to activate the JNK pathwayin neurons. For example, activation of JNKs and phosphorylation of c-junhas been shown in brains of rats subjected to axotomy or ischemia withreperfusion, where neuronal cell loss was observed (Herdegen T., ClaretF.-X., Kallunki, T., Matin-Villalba A., Winter C., Hunter T. and KarinM. J. Neurosci. 18:5124-5135, 1998). Further, inhibition of the mixedlineage kinase (MLK)-3, an upstream kinase in the JNK pathway, byCEP-1347 prevented motoneuron cell death following growth factorwithdrawal in vitro (Maroney A. C., Glicksman M. A., Basma A. N., WaltonK. M., Knight Jr. E., Murphy C. A., Bartlett B. A., Finn J. P., AngelesT., Matsuda Y., Neff N. T. and Dionne C. A., J. Neurosci. 18:104-111,1998), protected cholinergic neurons following excitotoxic injury of thenucleus basalis magnocellularis (Saporito M. S., Brown, E. R., Miller M.S., Murakata C., Neff N. H., Vaught J. L., and Carswell S. Neuroscience86:461-472, 1998), and blocked the degeneration of midbrain dopamineneurons in mice treated with the neurotoxin, 1-methyl-4-phenyltetrahydropyridine (Saporito M. S., Brown E. M., Miller M. S. andCarswell S. J. Pharm. Exp. Ther., 1999). While JNK1 and JNK2 enzymeshave a widespread tissue distribution, JNK3 is selectively expressed inbrain and to a lesser extent in the heart and testis (Dong C., Yang D.,Wysk M., Whitmarsh A., Davis R., and Flavell R. Science 270:1-4, 1998).Because of this restricted distribution, JNK3 may be the prevailingkinase mediating neuronal apoptosis. In support of JNK3's involvement inneuronal apoptosis, disruption of the gene encoding JNK3 in mice confersresistance to kainic acid-induced seizures and subsequent hippocampalneuronal cell death (Yang D. D., Kuan C.-Y., Whitmarsh A. J., Rincon M.,Zheng T. S., Davis R. J., Rakic P. and Flavell R. A. Nature 389:865-870,1997). Mounting evidence points to a role for the JNK pathway inneuronal apoptosis. Therefore, selective JNK inhibitors should preventneuronal cell death observed in disorders and diseases of the CNS.

Accordingly, there is a need in the art for treating or preventing adisease associated with modulation of JNK, compositions comprisingmodulators of JNK, and methods of modulating INK and treating orpreventing a disorder that is alleviated by modulation of JNK. Thepresent invention fulfills these needs, and provides further relatedadvantages.

Citations or identification of any reference in Section 2 of thisapplication is not to be construed that such reference is prior art tothe present application.

3. SUMMARY OF THE INVENTION

The present invention encompasses novel compounds having the generalFormula:

or pharmaceutically acceptable salts thereof,

being (i) unsubstituted, (ii) monosubstituted and having a firstsubstituent, or (iii) disubstituted and having a first substituent and asecond substituent;

the first or second substituent, when present, is at the 3, 4, 5, 7, 8,9, or 10 position;

the first and second substituent, when present, are independently alkyl,hydroxy, halogen, nitro, trifluoromethyl, sulfonyl, carboxyl,alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl,cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy,aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a grouprepresented by formula (a), (b), (c), (d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl alkoxycarbonylalkyl, amino, mono-alkylamino,di-alkylamino, arylamino, arylalkylamino, cycloalkylamino,cycloalkylalkylamino, aminoalkyl, mono-alkylaminioalkyl, ordi-alkylaminoalkyl.

In one embodiment, the first and second substituent of compounds ofFormula I, when present, are independently alkyl, halogen, nitro,trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl,aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy,alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy,di-alkylaminoalkoxy, or a group represented by formula (a), (b), (c),(d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, amino, mono-alkylamino, di-alkylamino, arylamino,arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl,mono-alkylaminioalkyl, or di-alkylaminoalkyl.

The present invention further provides novel compounds of the Formula:

or pharmaceutically acceptable salts thereof,

being (i) unsubstituted, (ii) monosubstituted and having a firstsubstituent, or (iii) disubstituted and having a first substituent and asecond substituent;

the first or second substituent, when present, is at the 3, 4, 5, 7, 8,9, or 10 position;

wherein the first and second substituent, when present, areindependently alkyl, hydroxy, halogen, nitro, trifluoromethyl, sulfonyl,carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy,arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy,aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a grouprepresented by formula (a), (b) (c), (d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, anddi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino,di-alkylamino, arylamino, arylalkylamino, cycloalkylamino,cycloalkylalkylamino, aminoalkyl, mono-alkylaminioalkyl,di-alkylaminoalkyl.

In one embodiment, the first and second substituent of compounds ofFormula II, when present, are independently alkyl, halogen, nitro,trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl,aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy,alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy,di-alkylaminoalkoxy, or a group represented by formula (a), (b), (c),(d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, amino, mono-alkylamino, di-alkylamino, arylamino,arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl,mono-alkylaminioalkyl, or di-alkylaminoalkyl.

The present invention further provides novel compounds of the Formula:

or pharmaceutically acceptable salts thereof,

being (i) monosubstituted and having a first substituent or (ii)disubstituted and having a first substituent and a second substituent;

the first or second substituent, when present, is at the 3, 4, 5, 7, 8,9, or 10 position;

wherein the first and second substituent, when present, areindependently alkyl, hydroxy, halogen, nitro, trifluoromethyl, sulfonyl,carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy,arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy,aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a grouprepresented by formula (a), (b), (c) (d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino,di-alkylamino, arylamino, arylalkylamino, cycloalkylamino,cycloalkylalkylamino, aminoalkyl, mono-alkylaminioalkyl, ordi-alkylaminoalkyl;

with the proviso that if the first substituent is halogen or alkoxy, thecompound is disubstituted.

In one embodiment, the first and second substituent of compounds ofFormula III, when present, are independently alkyl, halogen, nitro,trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl,aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy,alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy,di-alkylaminoalkoxy, or a group represented by formula (a), (b), (c),(d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, amino, mono-alkylamino, di-alkylamino, arylamino,arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl,mono-alkylaminioalkyl, or di-alkylaminoalkyl;

with the proviso that if the first substituent is halogen or alkoxy, thecompound is disubstituted.

The present invention further provides novel compounds of the Formula:

or pharmaceutically acceptable salts thereof,

being (i) monosubstituted and having a first substituent present at the5, 7, or 9 position, (ii) disubstituted and having a first substituentpresent at the 5 position and a second substituent present at the 7position, (iii) disubstituted and having a first substituent present atthe 5 position and a second substituent present at the 9 position, or(iv) disubstituted and having a first substituent present at the 7position and a second substituent present at the 9 position;

wherein the first and second substituent, when present, areindependently alkyl, hydroxy, halogen, nitro, trifluoromethyl, sulfonyl,carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy,arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy,aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a grouprepresented by formula (a), (b), (c), (d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino,di-alkylamino, arylamino, arylalkylamino, cycloalkylamino,cycloalkylalkylamino, aminoalkyl, mono-alkylaminioalkyl, ordi-alkylaminoalkyl;

with the proviso that when the first substituent is present at the 7position and is halogen, nitro, or a group represented by the formula(a), the compound is disubstituted.

In one embodiment, the first and second substituent of compounds ofFormula IV, when present, are independently alkyl, halogen, nitro,trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl,aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy,alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy,di-alkylaminoalkoxy, or a group represented by formula (a), (b), (c),(d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, amino, mono-alkylamino, di-alkylamino, arylamino,arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl,mono-alkylaminoalkyl, or di-alkylaminoalkyl;

with the proviso that when the first substituent is present at the 7position and is halogen, nitro, or a group represented by the formula(a), the compound is disubstituted.

The present invention further provides novel compounds of the Formula:

or pharmaceutically acceptable salts thereof,

being (i) monosubstituted and having a first substituent present at the5, 7, or 9 position, (ii) disubstituted and having a first substituentpresent at the 5 position and a second substituent present at the 9position, (iii) disubstituted and having a first substituent present atthe 7 position and a second substituent present at the 9 position, or(iv) disubstituted and having a first substituent present at the 5position and a second substituent present at the 7 position;

wherein the first and second substituent, when present, areindependently alkyl, hydroxy, halogen, nitro, trifluoromethyl, sulfonyl,carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy,arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy,aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a grouprepresented by formula (a), (b), (c), (d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino,di-alkylamino, arylamino, arylalkylamino, cycloalkylamino,cycloalkylalkylamino, aminoalkyl, mono-alkylaminioalkyl, ordi-alkylaminoalkyl;

with the proviso that if the first substituent is halogen or alkoxy,then the compound is disubstituted;

with the further proviso that if the compound is monosubstituted and hasa first substituent at the 5 or 7 position, then the first substituentis a group represented by the formula (e) or (f);

and with the further proviso that if the compound is disubstituted andhas a substituent present at the 7 position, then the substituentpresent at the 7 position is not a group represented by the formula (a)or (c).

In one embodiment, the first and second substituent of compounds ofFormula V, when present, are independently alkyl, halogen, nitro,trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl,aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy,alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy,di-alkylaminoalkoxy, or a group represented by formula (a), (b), (c),(d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alky, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, amino, mono-alkylamino, di-alkylamino, arylamino,arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl,mono-alkylaminoalkyl, or di-alkylaminoalkyl;

with the proviso that if the first substituent is halogen or alkoxy,then the compound is disubstituted;

with the further proviso that if the compound is monosubstituted and hasa first substituent at the 5 or 7 position, then the first substituentis a group represented by the formula (e) or (f);

and with the further proviso that if the compound is disubstituted andhas a substituent present at the 7 position, then the substituentpresent at the 7 position is not a group represented by the formula (a)or (c).

The compounds of Formulas (I)-(V), and pharmaceutically acceptable saltsthereof, are useful for modulating JNK. Accordingly, the compounds ofFormulas (I)-(V), and pharmaceutically acceptable salts thereof, areuseful for treating or preventing a disease associated with themodulation of JNK. Preferably, the compounds of Formulas (I)-(V), andpharmaceutically acceptable salts thereof, inhibit JNK. The compounds ofFormula (I)-(V), or pharmaceutically acceptable salts thereof, are alsouseful for treating cancer; rheumatoid arthritis; rheumatoidspondylitis; osteoarthritis; gout; asthma; bronchitis; cystic fibrosis;inflammatory bowel disease; irritable bowel syndrome; mucous colitis;ulcerative colitis; Crohn's disease; gastritis; esophagitis; hepatitis;multiple sclerosis; endotoxin shock; psoriasis; eczema; dermatitis;atherosclerosis; restenosis following angioplasty; left ventricularhypertrophy; myocardial infarction; stroke; ischemic damage to theheart, kidney, liver, or brain; transplant rejection; systemic lupuserythomatosus; pancreatitis; chronic obstructive pulmonary disease;conjunctive heart failure or a central or peripheral neurologicaldegenerative disorder.

The invention also relates to pharmaceutical compositions comprising acompound of Formula (I)-(V), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or vehicle.

The present invention further relates to pharmaceutical compositionscomprising:

(A) a compound having the formula:

or a pharmaceutically acceptable salt thereof,

wherein R₀ is —O—, —S—, —S(O)—, —S(O)₂— or —CH₂—;

the compound being (i) unsubstituted, (ii) monosubstituted and having afirst substituent, or (iii) disubstituted and having a first substituentand a second substituent;

the first or second substituent, when present, is at the 3, 4, 5, 7, 8,9, or 10 position, wherein the first and second substituent, whenpresent, are independently alkyl, hydroxy, halogen, nitro,trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl,aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy,alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy,di-alkylaminoalkoxy, or a group represented by formula (a), (b), (c),(d), (e), or (f):.

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino,di-alkylamino, arylamino, arylalkylamino, cycloalkylamino,cycloalkylalkylamino, aminoalkyl, mono-alkylaminioalkyl, ordi-alkylaminoalkyl; and

(B) a pharmaceutically acceptable carrier or vehicle.

In one embodiment, the first or second substituent of compounds ofFormula VI, when present, is at the 3, 4, 5, 7, 8, 9, or 10 position,wherein the first and second substituent, when present, areindependently alkyl, halogen, nitro, trifluoromethyl, sulfonyl,carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy,arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy,aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a grouprepresented by formula (a), (b), (c), (d), (e), or (f):.

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, amino, mono-alkylamino, di-alkylamino, arylamino,arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl,mono-alkylaminioalkyl, or di-alkylaminoalkyl.

The compositions are useful for modulating JNK. Accordingly, thecompositions are useful for treating or preventing a disease associatedwith the modulation of JNK. Preferably, the compositions inhibit JNK.The compositions are also useful for treating cancer; rheumatoidarthritis; rheumatoid spondylitis; osteoarthritis; gout; asthma;bronchitis; cystic fibrosis; inflammatory bowel disease; irritable bowelsyndrome; mucous colitis; ulcerative colitis; Crohn's disease;gastritis; esophagitis; hepatitis; multiple sclerosis; endotoxin shock;psoriasis; eczema; dermatitis; atherosclerosis; restenosis followingangioplasty; left ventricular hypertrophy; myocardial infarction;stroke; ischemic damage to the heart, kidney, liver, or brain;transplant rejection; systemic lupus erythomatosus; pancreatitis;chronic obstructive pulmonary disease; conjunctive heart failure or acentral or peripheral neurological degenerative disorder.

The invention also relates to methods for treating or preventing adisease associated with modulation of JNK, which comprises administeringto a patient in need thereof an effective amount of a compound of theFormula (I)-(VI), or a pharmaceutically acceptable salt thereof.

The invention further relates to a method for treating or preventing adisorder, which comprises administering to a patient in need thereof aneffective amount of a compound of the Formula (I)-(VI), or apharmaceutically acceptable salt thereof, wherein the disorder iscancer; rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis;gout; asthma; bronchitis; cystic fibrosis; inflammatory bowel disease;irritable bowel syndrome; mucous colitis; ulcerative colitis; Crohn'sdisease; gastritis; esophagitis; hepatitis; multiple sclerosis;endotoxin shock; psoriasis; eczema; dermatitis; atherosclerosis;restenosis following angioplasty; left ventricular hypertrophy,myocardial infarction; stroke; ischemic damage to the heart, kidney,liver, or brain; transplant rejection; systemic lupus erythomatosus;pancreatitis; chronic obstructive pulmonary disease; conjunctive heartfailure or a central or peripheral neurological degenerative disorder.

The present invention further relates to a method for treating orpreventing cancer, which comprises administering to a patient in needthereof an effective amount of a compound of the Formula (I)-(VI), or apharmaceutically acceptable salt thereof.

The present invention may be understood more fully by reference to thebrief description of the drawings, detailed description, and examples,which are intended to exemplify non-limiting embodiments of theinvention.

4. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 describes the effect of Compound CC on dopamine uptake in ratventral mesencephalan neurons following exposure to the neurotoxin6-OHDA. In FIG. 1♦ represents ventral mesencephalan neurons treated onlywith 6-OHDA and -♦- represents ventral mesencephalan neurons treatedwith 6-OHDA and Compound CC.

5. DETAILED DESCRIPTION OF THE INVENTION 5.1 Definitions

As used herein, the terms used above have the following meaning:

“Alkyl” means a straight chain or branched, saturated or unsaturatedchain having from 1 to 8 carbon atoms. Representative saturated alkylgroups include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl, andlonger alkyl groups, such as heptyl, and octyl. An alkyl group can beunsubstituted or substituted. Unsaturated alkyl groups include alkenylgroups and alkynyl groups, discussed below.

An “alkenyl group” means a monovalent unbranched or branched hydrocarbonchain having one or more double bonds therein. The double bond of analkenyl group can be unconjugated or conjugated to another unsaturatedgroup. Suitable alkenyl groups include, but are not limited to,(C₂-C₆)alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl,butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl,4-(2-methyl-3-butene)-pentenyl. An alkenyl group can be unsubstituted orsubstituted.

An “alkynyl group” means a monovalent unbranched or branched hydrocarbonchain having one or more triple bonds therein. The triple bond of analkynyl group can be unconjugated or conjugated to another unsaturatedgroup. Suitable alkynyl groups include, but are not limited to,(C₂-C₆)alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl,hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and4-butyl-2-hexynyl. An alkynyl group can be unsubstituted or substituted.

“Halogen” means fluorine, chlorine, bromine, or iodine.

“Trifluoromethyl” means —CF₃.

“Sulfonyl” means —SO₃H;

“Carboxyl” means —COOH.

“Alkoxy” means —O-(alkyl), wherein alkyl is defined above.

“Alkoxyalkoxy” means —O-(alkyl)-O-(alkyl), wherein each “alkyl” isindependently an alkyl group defined above. Preferably, akoxyalkoxy is—OCH₂OCH₃ or —OCH₂CH₂OCH₃.

“Alkoxycarbonyl” means —C(═O)O-(allyl), wherein alkyl is defined above.

“Alkoxycarbonylalkyl” means -(alkyl)-C(═O)O-(alkyl), wherein alkyl isdefined above.

“Alkoxyalkyl” means -(alkyl)-O-(alkyl), wherein each “alkyl” isindependently an alkyl group defined above. Preferably, alkoxyalkyl is—CH₂OCH₃ or —CH₂OCH₂CH₃.

“Aryl” means a carbocyclic or heterocyclic aromatic group containingfrom 5 to 10 ring atoms. The ring atoms of a carbocyclic aromatic groupare all carbon atoms, and include, but are not limited to, phenyl,tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as wellas benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.A carbocyclic aromatic group can be unsubstituted or substituted.Preferably, the carbocyclic aromatic group is a phenyl group. The ringatoms of a heterocyclic aromatic group contains at least one heteroatom,preferably 1 to 3 heteroatoms, independently selected from nitrogen,oxygen, and sulfur. Illustrative examples of heterocyclic aromaticgroups include, but are not limited to, pyridinyl, pyridazinyl,pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl,(1,2,3,)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl,indolyl, oxetanyl, azepinyl, piperazinyl, morpholinyl, dioxanyl,thietanyl and oxazolyl. A heterocyclic aromatic group can beunsubstituted or substituted. Preferably, a heterocyclic aromatic is amonocyclic ring, wherein the ring comprises 2 to 5 carbon atoms and 1 to3 heteroatoms.

“Aryloxy” means —O-aryl group, wherein aryl is as defined above. Anaryloxy group can be unsubstituted or substituted. Preferably, the arylring of an aryloxy group is a phenyl group.

“Arylalkyl” means -(alkyl)-(aryl), wherein alkyl and aryl are definedabove. Preferably arylalkyl is benzyl (i.e., —CH₂-phenyl) or—CH₂-pyrindinyl.

“Arylalkyloxy” means —O-(alkyl)-(aryl), wherein alkyl and aryl aredefined above. Preferably, arylalkyloxy is —O-benzyl or—O—CH₂-pyridinyl.

“Cycloalkyl” means a monocyclic or polycyclic saturated ring comprisingcarbon and hydrogen atoms and having no carbon-carbon multiple bonds.Examples of cycloalkyl groups include, but are not limited to,(C₃-C₇)cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes.A cycloalkyl group can be unsubstituted or substituted. Preferably, thecycloalkyl group is a monocyclic ring or bicyclic ring.

“Cycloalkyloxy” means —O-(cycloalkyl), wherein cycloalkyl is definedabove.

“Cycloalkylalkyloxy” means —O-(alkyl)-(cycloalkyl), wherein cycloalkyland alkyl are defined above. Preferably, cycloalkylalkyloxy is—OCH₂-cyclohexyl.

“Alkylidene” means the divalent radical —C_(n)H_(2n)—, wherein n is aninteger from 1 to 8, such as —CH₂—, —CH₂CH₂—, —CH₂—CH₂—CH₂—,—CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—, and the like, unsubstituted orsubstituted with one or more alkyl groups.

“Heteroatom-containing alkylidene” means an alkylidene wherein at leastone carbon atom is replaced by a heteroatom selected from nitrogen,oxygen, or sulfur, such as —CH₂CH₂OCH₂CH₂—, and the like, unsubstitutedor substituted with one or more alkyl groups.

“Aminoalkoxy” means —O-(alkyl)-NH₂, wherein alkyl is defined above.

“Mono-alkylamino” means —NH(alkyl), wherein alkyl is defined above.

“Di-alkylamino” means —N(alkyl)(alkyl), wherein each “alkyl” isindependently an alkyl group defined above.

“Mono-alkylaminoalkoxy” means —O-(alkyl)-NH(alkyl), wherein each “alkyl”is independently an alkyl group defined above.

“Di-alkylaminoalkoxy” means —O-(alkyl)N(alkyl)(alkyl), wherein each“alkyl” is independently an alkyl group defined above.

“Arylamino” means —NH(aryl), wherein aryl is defined above.

“Arylalkylamino” means —NH-(alkyl)-(aryl), wherein alkyl and aryl aredefined above. Preferably, arylalkylamino is —NH-benzyl or—NHCH₂-pyridinyl.

“Alkylamino” means —NH(alkyl), wherein alkyl is defined above.

“Cycloalkylamino” means —NH-(cycloalkyl), wherein cyclohexyl is definedabove.

“Cycloalkylalkylamino” means —NH-(alkyl)-(cycloalkyl), wherein alkyl andcloalkyl are defined above. Preferably, cycloalkylalkylamino is—NHCH₂-cyclohexyl.

“Aminoalkyl” means -(alkyl)-NH₂, wherein alkyl is defined above.

“Mono-alkylaminoalkyl” means -(alkyl)-NH(alkyl), wherein each “alkyl” isindependently an allyl group defined above.

“Di-alkylaminoalkyl” means -(alkyl)-N(alkyl)(alkyl), wherein each“alkyl” is independently an alkyl group defined above.

The phrase “modulation of JNK” or “by modulating JNK” means theinhibition or activation, preferably the inhibition, of a protein andall isoforms thereof expressed by JNK 1, JNK 2, and JNK 3 genes.

By “JNK” is meant a protein and all isoforms thereof expressed by JNK 1,JNK 2, and JNK 3 genes.

The phrase “pharmaceutically acceptable salt(s),” as used hereinincludes, but is not limited to, salts of acidic or basic groups thatcan be present in compounds of Formula (I)-(VI). Compounds that arebasic in nature are capable of forming a wide variety of salts withvarious inorganic and organic acids. The acids that can be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions. Suitable organic acidsinclude, but are not limited to, maleic, fumaric, benzoic, ascorbic,succinic, acetic, trifluoroacetic, formic, oxalic, propionic, tartaric,salicylic, citric, gluconic, lactic, mandelic, cinnamic, oleic, tannic,aspartic, stearic, palmitic, glycolic, glutamic, gluconic, glucaronic,saccharic, isonicotinic, methanesulfonic, ethanesulfonic,p-toluenesulfonic, benzenesulfonic acids, and pamoic (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate) acids. Suitable inorganicacids include hydrochloric, hydrobromic, hydroiodic, sulfuric,phosphoric, and nitric acids. Compounds that include an amine moiety canform pharmaceutically acceptable salts with various amino acids, inaddition to the acids mentioned above. Compounds that are acidic innature are capable of forming base salts with various pharmacologicallyacceptable cations. Examples of such salts include alkali metal oralkaline earth metal salts and, particularly, calcium, magnesium,sodium, lithium, zinc, potassium, and iron salts. Thus, the term“pharmaceutically acceptable salt(s)” of a compound of Formula (I)-(VI)is intended to encompass any and all acceptable salt forms.

5.2 Novel Compounds 5.2.1 Compounds of Formula (I)

The present invention encompasses novel compounds having the generalFormula (I):

and pharmaceutically acceptable salts thereof,

being (i) unsubstituted, (ii) monosubstituted and having a firstsubstituent, or (iii) disubstituted and having a first substituent and asecond substituent;

the first or second substituent, when present, is at the 3, 4, 5, 7, 8,9, or 10 position;

wherein the first and second substituent, when present, areindependently alkyl, hydroxy, halogen, nitro, trifluoromethyl, sulfonyl,carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy,arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy,aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a grouprepresented by formula (a), (b), (c), (d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino,di-alkylamino, arylamino, arylalkylamino, cycloalkylamino,cycloalkylalkylamino, aminoalkyl, mono-alkylaminioalkyl, ordi-alkylaminoalkyl.

In one embodiment, the first and second substituent of compounds ofFormula I, when present, are independently alkyl, halogen, nitro,trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl,aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy,alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy,di-alkylaminoalkoxy, or a group represented by formula (a), (b), (c),(d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, amino, mono-alkylamino, di-alkylamino, arylamino,arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl,mono-alkylaminioalkyl, or di-alkylaminoalkyl.

A preferred subclass of the compounds of Formula (I) is that wherein thefirst or second substituent are present at the 5, 7, or 9 position. Morepreferably, the first or second substituent are present at the 5 or 7position.

A second preferred class of compounds of formula (I) is that wherein:

the first or second substituent are present at the 5, 7, or 9 position;

the first or second substituent are independently alkoxy, aryloxy,aminoalkyl, mono-alkylaminoalkyl, di-alkylaminoalkyl, or a grouprepresented by the formula (a), (c), (d), (e), or (f);

R₃ and R₄ are independently hydrogen, alkyl, cycloalkyl, aryl,arylalkyl, or cycloalkylalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or cycloalkylalkyl.

5.2.2 Compounds of Formula (II)

The present invention encompasses novel compounds having the generalFormula (II):

and pharmaceutically acceptable salts thereof,

being (i) unsubstituted, (ii) monosubstituted and having a firstsubstituent, or (ii) disubstituted and having a first substituent and asecond substituent;

the first or second substituent, when present, is at the 3, 4, 5, 7, 8,9, or 10 position;

wherein the first and second substituent, when present, areindependently alkyl, halogen, hydroxy, nitro, trifluoromethyl, sulfonyl,carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy,arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy,aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a grouprepresented by formula (a), (b) (c), (d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino,di-alkylamino, arylamino, arylalkylamino, cycloalkylamino,cycloalkylalkylamino, aminoalkyl, mono-alkylaminioalkyl, ordi-alkylaminoalkyl.

In one embodiment, the first and second substituent of compounds ofFormula II, when present, are independently alkyl, halogen, nitro,trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl,aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy,alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy,di-alkylaminoalkoxy, or a group represented by formula (a), (b) (c),(d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, amino, mono-alkylamino, di-alkylamino, arylamino,arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl,mono-alkylaminioalkyl, or di-alkylaminoalkyl.

A preferred subclass of the compounds of Formula (II) is that whereinthe first or second substituent are present at the 5, 7, or 9 position.More preferably, the first or second substituent are present at the 5 or7 position.

A second preferred subclass of the compounds of Formula (II) is thatwherein:

the first or second substituent are independently alkoxy, aryloxy, or agroup represented by the formula (a), (c), (d), (e), or (f);

R₃ and R₄ are independently hydrogen, alkyl, cycloalkyl, aryl,arylalkyl, or cycloalkylalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or cycloalkylalkyl.

5.2.3 Compounds of Formula (III)

The present invention encompasses novel compounds having the generalFormula (III):

and pharmaceutically acceptable salts thereof,

being (i) monosubstituted and having a first substituent or (ii)disubstituted and having a first substituent and a second substituent;

the first or second substituent, when present, is at the 3, 4, 5, 7, 8,9, or 10 position;

wherein the first and second substituent, when present, areindependently alkyl, halogen, hydroxy, nitro, trifluoromethyl, sulfonyl,carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy,arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy,aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a grouprepresented by formula (a), (b), (c) (d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino,di-alkylamino, arylamino, arylalkylamino, cycloalkylamino,cycloalkylalkylamino, aminoalkyl, mono-alkylaminioalkyl, ordi-alkylaminoalkyl;

with the proviso that if the first substituent is halogen or alkoxy, thecompound is disubstituted.

In one embodiment, the first and second substituent of compounds ofFormula III, when present, are independently alkyl, halogen, nitro,trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl,aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy,alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy,di-alkylaminoalkoxy, or a group represented by formula (a), (b), (c)(d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, amino, mono-alkylamino, di-alkylamino, arylamino,arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl,mono-alkylaminioalkyl, or di-alkylaminoalkyl;

with the proviso that if the first substituent is halogen or alkoxy, thecompound is disubstituted.

A preferred subclass of the compounds of Formula (III) is that whereinthe first or second substituent are present at the 5, 7, or 9 position.More preferably, the first or second substituent are present at the 5 or7 position.

A second preferred subclass of the compounds of Formula (m) is thatwherein:

the first or second substituent are independently alkoxy, aryloxy,aminoalkyl, mono-alkylaminoalkyl, di-alkylaminoalkyl, or a grouprepresented by the formula (a), (c), (d), (e), or (f);

R₃ and R₄ are independently hydrogen, alkyl, cycloalkyl, aryl,arylalkyl, or cycloalkylalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or cycloalkylalkyl.

5.2.4 Compounds of Formula (IV)

The present invention encompasses novel compounds having the generalFormula (IV):

and pharmaceutically acceptable salts thereof,

being (i) monosubstituted and having a first substituent present at the5, 7, or 9 position, (ii) disubstituted and having a first substituentpresent at the 5 position and a second substituent present at the 7position, (iii) disubstituted and having a first substituent present atthe 5 position and a second substituent present at the 9 position, or(iv) disubstituted and having a first substituent present at the 7position and a second substituent present at the 9 position;

wherein the first and second substituent, when present, areindependently alkyl, halogen, hydroxy, nitro, trifluoromethyl, sulfonyl,carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy,arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy,aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a grouprepresented by formula (a), (b), (c), (d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino,di-alkylamino, arylamino, arylalkylamino, cycloalkylamino,cycloalkylalkylamino, aminoalkyl, mono-alkylaminioalkyl, ordi-alkylaminoalkyl;

with the proviso that when the first substituent is present at the 7position and is halogen, nitro, or a group represented by the formula(a), the compound is disubstituted.

In one embodiment, the first and second substituent of compounds ofFormula IV, when present, are independently alkyl, halogen, nitro,trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl,aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy,alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy,di-alkylaminoalkoxy, or a group represented by formula (a), (b), (c),(d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, amino, mono-alkylamino, di-alkylamino, arylamino,arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl,mono-alkylaminioalkyl, or di-alkylaminoalkyl;

with the proviso that when the first substituent is present at the 7position and is halogen, nitro, or a group represented by the formula(a), the compound is disubstituted.

A preferred class of the compounds of Formula (V) is that wherein thefirst or second substituent are present at the 5 or 7 position.

A second preferred subclass of the compounds of Formula (IV) is thatwherein the first or second substituent are independently alkyl,trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl,aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy,alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy,di-alkylaminoalkoxy, or a group represented by formula (a), (c), (d),(e), or (f).

Another preferred subclass of the compounds of Formula (IV) is thatwherein:

the first and second substituent are independently alkoxy, aryloxy, or agroup represented by the formula (a), (c), (d), (e), or (f);

R₃ and R₄ are independently hydrogen, alkyl, cycloalkyl, aryl,arylalkyl, or cycloalkylalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, alkoxycarbonyl, orcycloalkylalkyl.

5.2.5 Compounds of Formula (V)

The present invention encompasses novel compounds having the generalFormula (V):

and pharmaceutically acceptable salts thereof,

being (i) monosubstituted and having a first substituent present at the5, 7, or 9 position, (ii) disubstituted and having a first substituentpresent at the 5 position and a second substituent present at the 9position, (iii) disubstituted and having a first substituent present atthe 7 position and a second substituent present at the 9 position, or(iv) disubstituted and having a first substituent present at the 5position and a second substituent present at the 7 position;

wherein the first and second substituent, when present, areindependently alkyl, halogen, hydroxy, nitro, trifluoromethyl, sulfonyl,carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy,arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy,aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a grouprepresented by formula (a), (b), (c), (d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino,di-alkylamino, arylamino, arylalkylamino, cycloalkylamino,cycloalkylalkylamino, aminoalkyl, mono-alkylaminioalkyl, ordi-alkylaminoalkyl;

with the proviso that if the first substituent is halogen or alkoxy,then the compound is disubstituted;

with the further proviso that if the compound is monosubstituted and hasa first substituent at the 5 or 7 position, then the first substituentis a group represented by the formula (e) or (f);

and with the further proviso that if the compound is disubstituted andhas a substituent present at the 7 position, then the substituentpresent at the 7 position is not a group represented by the formula (a)or (c).

In one embodiment, the first and second substituent of compounds ofFormula V, when present, are independently alkyl, halogen, nitro,trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl,aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy,alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy,di-alkylaminoalkoxy, or a group represented by formula (a), (b), (c),(d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, amino, mono-alkylamino, di-alkylamino, arylamino,arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl,mono-alkylaminioalkyl, or di-alkylaminoalkyl;

with the proviso that if the first substituent is halogen or alkoxy,then the compound is disubstituted;

with the further proviso that if the compound is monosubstituted and hasa first substituent at the 5 or 7 position, then the first substituentis a group represented by the formula (e) or (f);

and with the further proviso that if the compound is disubstituted andhas a substituent present at the 7 position, then the substituentpresent at the 7 position is not a group represented by the formula (a)or (c).

A preferred subclass of the compounds of Formula (V) is that wherein thefirst or second substituent are present at the 5 or 7 position.

A second preferred subclass of the compounds of Formula (V) is thatwherein the compound of Formula (V) is disubstituted and at least one ofthe substituents is a group represented by the formula (d) or (f).

Another preferred class of the compounds of Formula (V) is that whereinthe compounds are monosubstituted. Most preferred are compounds that aremonosubstituted at the 5 or 7 position with a group represented by theformula (e) or (f).

The compounds of Formulas (I)-(V), and pharmaceutically acceptable saltsthereof, are useful for modulating JNK. Accordingly, the compounds ofFormulas (I)-(V), and pharmaceutically acceptable salts thereof, areuseful for treating or preventing a disease associated with themodulation of JNK. Preferably, the compounds of Formulas (I)-(V), andpharmaceutically acceptable salts thereof, inhibit JNK. The compounds ofFormula (I)-(V), or pharmaceutically acceptable salts thereof, are alsouseful for treating cancer; rheumatoid arthritis; rheumatoidspondylitis; osteoarthritis; gout; asthma; bronchitis; cystic fibrosis;inflammatory bowel disease; irritable bowel syndrome; mucous colitis;ulcerative colitis; Crohn's disease; gastritis; esophagitis; hepatitis;multiple sclerosis; endotoxin shock; psoriasis; eczema; dermatitis;atherosclerosis; restenosis following angioplasty; left ventricularhypertrophy; myocardial infarction; stroke; ischemic damage to theheart, kidney, liver, or brain; transplant rejection; systemic lupuserythomatosus; pancreatitis; chronic obstructive pulmonary disease;conjunctive heart failure or a central or peripheral neurologicaldegenerative disorder.

5.3 Synthesis 5.3.1 Synthesis of the Compounds of Formula (I)

Compounds of Formula (I), the compound of Formula (I) being definedabove, can be prepared in a two step procedure depicted in ReactionScheme 1 below.

The first step involves halogenation of 1-methylanthraquinone or anappropriately monosubstituted or disubstituted 1-methylanthroquinonewith a halogenating agent in a suitable solvent, or in the absence ofsolvent, at temperatures from about 25° C. to about 200° C. for about 1to about 16 hours. Representative halogenating agents include, but arenot limited to, thionyl chloride, thionyl bromide, POCl₃, POBr₃,N-bromosuccinimide, and N-chlorosuccinimide. Suitable solvents are, forexample, benzene, tetrahydrofuran (THF), and ether. The resultinghalogenated intermediate is then treated with ammonia in a suitablesolvent at temperatures from about 25° C. to about 200° C. for about 1to about 16 hours. Suitable solvents are, for example, ethanol andmethanol.

The compounds of Formula (I) can also be prepared by the two stepprocedure depicted in Reaction Scheme 2 below.

The first step involves reacting anthroquinone or an appropriatelymonosubstituted or disubstituted anthroquinone with trichloroaceticacid-(hydroxymethyl-amide) in the presence of an acid, such as sulfuricacid or hydrochloric acid, in a suitable solvent or in the absence ofsolvent, to provide a 2,2,2-trichloroacetyl-aminomethyl substitutedanthraquinone. Suitable solvents are, for example, nitrobenzene,dichlorobenzene, and nitromethane. The second step involves reacting the2,2,2-trichloroacetyl-aminomethyl substituted anthraquinone with a basecatalyst in a suitable solvent. Suitable base catalysts include, but arenot limited to, sodium hydroxide, potassium hydroxide, potassiumcarbonate, sodium methoxide, and sodium ethoxide. Suitable solvents are,for example, water, methanol, and ethanol.

5.3.2 Synthesis of the Compounds of Formula (II)

Compounds of Formula (II), the compound of Formula (II) being definedabove, can be prepared by oxidizing compounds of Formula (V) with astoichiometric amount of a mild oxidizing agent in a suitable solvent attemperatures from about 0° C. to about 200° C. for about 1 to about 24hours. Suitable reducing agents include, but are not limited to, sodiumhypochlorite, meta-chloroperbenzoic acid, pyridinium chlorochromate,dipyridine Cr(VI) oxide, and pyridinium dichromate. Suitable solventsare, for example, hydrocarbon solvents and chlorinated solvents, such asmethylene chloride and carbon tetrachloride.

5.3.3 Synthesis of the Compounds of Formula (III)

Compounds of Formula (III), the compound of Formula (III) being definedabove, can be prepared by condensing anthroquinone or an appropriatelymonosubstituted or disubstituted anthroquinone, having a leaving group,X, at the 1 position, with hydroxylamine as depicted in Reactions Scheme3 below.

The reaction is carried out in a suitable solvent at temperatures fromabout 0° C. to about 200° C. for about 1 to about 16 hours. Suitablesolvents are, for example, ethanol, methanol, and THF. Suitable leavinggroups include, but are not limited to fluoro, chloro, bromo, iodo,nitro, methanesulfonyloxy, tosyloxy, and phenoxy.

5.3.4 Synthesis of the Compounds of Formula (IV)

Compounds of Formula (IV), the compound of Formula (IV) being definedabove, can be prepared by oxidizing compounds of Formula (V) with anexcess of the oxidizing agents used to prepare the compounds of Formula(II). The reaction is conducted in a suitable solvent at temperaturesfrom about 0° C. to about 200° C. for about 1 to about 24 hours.Suitable solvents are, for example, hydrocarbon solvents and chlorinatedsolvents, such as methylene chloride, and carbon tetrachloride.

Compounds of Formula (IV) can also be prepared by oxidation of thecompounds of Formula (V) with CrO₃ in a suitable solvent at temperaturesfrom about 0° to about 100° C. for about 1 to about 16 hours, asdepicted in Reaction Scheme 4 below.

Suitable solvents are, for example, acetic acid, formic acid, an aqueousHCl.

5.3.5 Synthesis of the Compounds of Formula (V)

Compounds of Formula (V), the compound of Formula (V) being definedabove, can be prepared by condensing anthroquinone or an appropriatelymonosubstituted or disubstituted anthroquinone with ammoniumthiocyanate, as depicted in Reaction Scheme 5 below.

The reaction is carried out in a suitable solvent at temperatures fromabout 0° C. to about 200° C. for about 1 to about 24 hours. Suitablesolvents are, for example, pyridine, dimethylformamide,dimethylsulfoxide (DMSO), and dioxane The resulting intermediate is thenreacted with ammonia in a suitable solvent, or in the absence ofsolvent, at temperatures from about 25° C. to about 200° C. for about 1to about 24 hours. Suitable solvents are, for example, ethanol,methanol, and water.

The compounds of Formula (V) can also be prepared by a two stepprocedure depicted in Reaction Scheme 6 below.

The first step involves condensing an appropriately substitutedanthroquinone having a leaving group, X, at the 1-position, with sodiumsulfide in the presence of ammonia in a suitable solvent. Representativeleaving groups include, but are not limited to fluoro, chloro, bromo,iodo, nitro, methanesulfonyloxy, tosyloxy, and phenoxy. Suitablesolvents are, for example, pyridine, dimethylformamide, methylenechloride, chloroform, ethanol, and dioxane. The reaction is carried outat temperatures from about 0° C. to about 200° C. for about 1 to about16 hours. The resulting intermediate is then treated with iodine and abase, such as, but not limited to, sodium acetate, sodium phosphate, orsodium bicarbonate in a suitable solvent. Suitable solvents are, forexample, benzene, toluene, nitrobenzene, dichlorobenzene, and xylenes.The reaction is carried out at temperatures from about 0° C. to about200° C. for about 1 to about 16 hours.

5.3.6 Synthesis of the Compounds of Formula (VI)

Compounds of Formula (VI), the compound of Formula (VI) being definedabove, with 5-amino substituents can be prepared by condensing anappropriately substituted compound of Formula (VI), having a leavinggroup, X, at the 5 position, with ammonia, a mono-substituted amine, ora di-substituted amine at temperatures from about 0° C. to about 250° C.for about 1 to about 16 hours, either in a suitable solvent or theabsence of a solvent as depicted in Reaction Scheme 7 below.

Representative leaving groups include, but are not limited to chloride,bromide, iodide, methanesulfonate, tosyl, benzenesulfonate, andtriflate. Suitable solvents are, for example, pyridine,dimethylformamide, dimethylsulfoxide, dichloroethane, chloroform,tetrahydrofuran, dioxane, diglyme, and triglyme. The reaction isconducted in the presence of an excess amount of the amine, or in thepresence of an acid quenching agent such as triethylamine,diisopropylethylamine, sodium bicarbonate, potassium carbonate, orsodium hydroxide.

The compound of Formula (VI), having a leaving group, X, at the 5position, wherein X is chloro can be prepared, for example, bycondensing 1,4-dichloroanthroquinone with ammonium thiocyanate using themethod described in Reaction Scheme 5.

Compounds of Formula (VI) with 5-amino substituents can also be preparedby condensing an appropriately substituted compound of Formula (VI) withan amino group at the 5-position with an alkyl group containing a goodleaving group, X, (R₃X) at temperatures from about 25° C. to about 250°C. for about 1 to about 24 hours, in a suitable solvent or in theabsence of solvent as depicted in Reaction Scheme 8 below.

Representative leaving groups include, but are not limited to, chloride,bromide, iodide, methanesulfonate, tosylate, benzenesulfonate, andtriflate. Suitable solvents are, for example, pyridine,dimethylformamide, dimethylsulfoxide, dichloroethane, chloroform,tetrahydrofuran, dioxane, diglyme, and triglyme. The reaction isconducted in the presence of an excess amount of the amine, or in thepresence of an acid quenching agent such as triethylamine,diisopropylethylamine, sodium bicarbonate, potassium carbonate, orsodium hydroxide.

Similarly, compounds of Formula (VI) with 7-amino substituents can beprepared by condensing an appropriately substituted compound of Formula(VI), having a leaving group, X, at the 7 position, with ammonia, amono-substituted amine, or a di-substituted amine at temperatures fromabout 0° C. to about 250° C. for about 1 to about 16 hours, either in asuitable solvent or the absence of a solvent as depicted in ReactionScheme 9 below.

Representative leaving groups include, but are not limited to, chloride,bromide, iodide, methanesulfonate, tosylate, benzenesulfonate, andtriflate. Suitable solvents are, for example, pyridine,dimethylformamide, dimethylsulfoxide, dichloroethane, chloroform,tetrahydrofuran, dioxane, diglyme, and triglyme. The reaction isconducted in the presence of an excess amount of the amine, or in thepresence of an acid quenching agent such as triethylamine,diisopropylethylamine, sodium bicarbonate, potassium carbonate, orsodium hydroxide.

Compounds of Formula (VI) with 7-amino substituents can also be preparedby condensing an appropriately substituted compound of Formula (VI) withan amino group at the 7-position with an alkyl group containing a goodleaving group, X, (R₃X) at temperatures of from about 25° C. to about250° C. for about 1 to about 24 hours, in a suitable solvent or in theabsence of solvent as depicted in Reaction Scheme 10 below.

Representative leaving groups include, but are not limited to, chloride,bromide, iodide, methanesulfonate, tosylate, benzenesulfonate, andtriflate. Suitable solvents are, for example, pyridine,dimethylformamide, dimethylsulfoxide, dichloroethane, chloroform,tetrahydrofuran, dioxane, diglyme, and triglyme. The reaction isconducted in the presence of an excess amount of the amine, or in thepresence of an acid quenching agent such as triethylamine,diisopropylethylamine, sodium bicarbonate, potassium carbonate, orsodium hydroxide.

Similarly, amine substituents at other positions on the aromatic ringcan be converted to substituted amines at their respective positions.Anthroquinones substituted with amine at other positions are known(Kopetschni, Wiesler Monatsh. Chem (1922), 43, 84; Shah et al., IndianJournal of Chemistry (1976), 14B, 625; Ayyangar, N., Lahoti, R. J.,Wagle, D. R. Indian Journal of Chemistry (1978), 16B, 1007).

Compounds of Formula (VI) with 5-carboxyamide substituents can beprepared by condensing an appropriately substituted compound of Formula(VI), having a carboxylic acid group at the 5 position, with ammonia, amono-substituted amine, or a di-substituted amine at temeratures fromabout 0° C. to about 100° C. for about 1 to about 16 hours using acoupling agent in a suitable solvent as depicted in Reaction Scheme 11below.

Representative coupling agents include, but are not limited todicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(HATU). Suitable solvents are, for example, methylene chloride,chloroform, toluene, dimethylformamide, and tetrahydrofuran.

The starting carboxylic acid may be prepared from a compound of Formula(VI) substituted at the 5 position with an amino group. The 5-aminogroup is converted to a nitrile with sodium nitrite in a suitablesolvent, such as water, methanol, tetrahydrofuran, or ethanol and anacid such as hydrochloric acid or sulfuric acid at temperatures fromabout 0° C. to about 100° C. for about 1 to about 10 hours followed bytreatment with copper cyanide/sodium cyanide in a suitable solvent suchas water, methanol, ethanol, ethyl acetate, or tetrahydrofuran attemperatures from about 0° C. to about 100° C. for about 1 to about 10hours. The nitrile can then be hydrolyzed with an acid such as aceticacid, formic acid, hydrochloric acid, or sulfuric acid at a temperaturefrom about 25° C. to about 100° C. for about 1 to about 24 hours toprovide the carboxylic acid. In a similar manner, carboxylic acid groupsat other positions on the aromatic ring can be converted to carboxamidesubstituents at their respective positions. Carboxylic acid groups atother positions on the aromatic ring can be obtained from compounds ofFormula (VI) having amines at other positions on the aromatic ring, asdiscussed above.

Compounds of Formula (VI) with 5-acylamino or 5-sulfonylaminosubstituents can be prepared by condensing an appropriately substitutedcompound of Formula (VI), having an amino group at the 5-position withan acid chloride, R₅COCl, or sulfonyl chloride R₅SO₂Cl, in a suitablesolvent at temperatures from about −20° C. to about 50° C. for about 0.5to about 16 hours as depicted in Reaction Scheme 12 below.

Similarly, compounds of Formula (VI) with 7-acylamino or 7-sulfonylaminosubstituents can be prepared by condensing an appropriately substitutedcompound of Formula (VI), having an amino group at the 7-position withan acid chloride, R₅COCl, or sulfonyl chloride R₅SO₂Cl, in a suitablesolvent at temperatures from about −20° C. to about 50° C. for about 0.5to about 16 hours as depicted in Reaction Scheme 13 below.

Suitable solvents are, for example, methylene chloride, chloroform,tetrahydrofuran, dioxane, pyridine, dimethylformamide, and ethylacetate. The reaction is conducted in the presence of an acid quenchingagent such as triethylamine, diisopropylethylamine, sodium bicarbonate,potassium carbonate, or sodium hydroxide.

Acylamino or sulfonylamino substituents groups at other positions on thearomatic ring can be obtained from compounds of Formula (VI) havingamines at other positions on the aromatic ring, as discussed above.

Compounds of Formula (VI) with 5-alkoxy substituents can be prepared bycondensing an appropriately substituted compound of Formula (VI), havinga hydroxy group at the 5-position with an alkyl group having a leavinggroup, X, (R₆X) in a suitable solvent at temperatures from about −20° C.to about 100° C. for about 0.5 to about 16 hours as depicted inReaction-Scheme 14 below.

Similarly, compounds of Formula (VI) with 7-alkoxy substituents can beprepared by condensing an appropriately substituted compound of Formula(VI) having a hydroxy group at the 7-position with an alkyl group havinga leaving group, X, (R₆X) in a suitable solvent at temperatures fromabout −20° C. to about 100° C. for about 0.5 to about 16 hours asdepicted in Reaction Scheme 15 below.

Representative leaving groups, X, include, but are not limited to,chloride, bromide, iodide, methanesulfonate, tosylate, benzenesulfonate,and triflate. Suitable solvents are, for example, methylene chloride,chloroform, tetrahydrofuran, dioxane, dimethylformamide, or ethylacetate.

The reaction is conducted in the presence of an acid quenching agentsuch as sodium hydride, triethylamine, diisopropylethylamine, sodiumbicarbonate, potassium carbonate, or sodium hydroxide.

The 5-hydroxyanthroquinones and 7-hydroxyanthroquinones can be preparedfrom the appropriately substituted 5-aminoanthroquinone andappropriately substituted 7-aminoanthroquinone, respectively. Theappropriately substituted 5-aminoanthroquinone or appropriatelysubstituted 7-aminoanthroquinone is converted to the alcohol with sodiumnitrite in a suitable solvent, such as water, methanol, tetrahydrofuran,or ethanol, and an acid, such as hydrochloric acid or sulfuric acid, attemperatures from about 0° to about 100° C. for about 1 to about 10hours followed by treatment with an acid, such as hydrochloric acid,sulfuric acid, or phosphoric acid, in water at temperatures from about0° C. to about 100° C. for about 1 to about 10 hours.

Alternately, the appropriately substituted 5-aminoanthroquinone orappropriately substituted 7-aminoanthroquinone can be heated attemperatures from about 100° C. to about 250° C. in water for about 1 toabout 24 hours to provide the compound of Formula (VI) with a hydroxygroup at the 5-position or 7-position, respectively. Hydroxyl groups atother positions on the aromatic ring can be obtained from compounds ofFormula (VI) having amines at other positions on the aromatic ring, asdiscussed above.

Disubstituted compounds of Formula (I)-(VI) can be obtained according toone or more of the reaction schemes above. Suitable anthraquinonestarting materials that are appropriately substituted are commerciallyavailable from a variety of sources or may be prepared by methods wellknown to those of ordinary skill in the art (See, e.g., Gallagher, P.,Contemp. Org. Synth. (1996), 3(5), 433-446; Krohn, K., Tetrahedron(1990), 46(2), 291-318; Vymetal, J., Chem. Listy (1982), 76(8), 846-68;Matsuoka, M., Yuki Gosei Kagaku Kyokaishi (1982), 40(2); Matsuura, A.,Nikkakyo Geppo (1978), 31(12); Chung, R. Kirk-Othmer Encycl. Chem.Technol., 3rd Ed., Editors: Grayson, M. and Eckloth, D., Wiley, NewYork, N.Y., (1978), 2, 708-57; and Chung, R. Kirk-Othmer Encycl. Chem.Technol., 3rd Ed., Editors: Grayson, M. and Eckroth, D., Wiley, NewYork, N.Y. (1978), 2, 700-7).

5.4 Pharmaceutical Compositions 5.4.1 Pharmaceutical CompositionsComprising a Compound of Formula (I)

The present invention encompasses compositions comprising a compound ofFormula (I), the compound of Formula (I) being defined above, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or vehicle.

In one embodiment, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is that wherein the first or second substituentis present at the 5, 7, or 9 position. Preferably, the first or secondsubstituent is present at the 5 or 7 position.

In another embodiment, the compound of Formula (I), or apharmaceutically acceptable salt thereof, is that wherein:

the first or second substituent is present at the 5, 7, or 9 position;

the first and second substituent are independently alkoxy, aryloxy,hydroxy or a group represented by the formula (a), (c), (d), (e), or(f);

R₃ and R₄ are independently hydrogen, alkyl, cycloalkyl, aryl,arylalkyl, or cycloalkylalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, alkoxycarbonylalkyl, aryl, arylalkyl,or cycloalkylalkyl.

In another embodiment, the compound of Formula (I), or apharmaceutically acceptable salt thereof, is that wherein:

the first or second substituent is present at the 5, 7, or 9 position;

the first and second substituent are independently alkoxy, aryloxy or agroup represented by the formula (a), (c), (d), (e), or (f);

R₃ and R₄ are independently hydrogen, alkyl, cycloalkyl, aryl,arylalkyl, or cycloalkylalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl or cycloalkylalkyl.

5.4.2 Pharmaceutical Compositions Comprising a Compound of Formula (II)

The present invention also encompasses compositions comprising acompound of Formula (II), the compound of Formula (II) being definedabove, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or vehicle.

In one embodiment, the compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, is that wherein the first or second substituentis present at the 5, 7, or 9 position. Preferably, the first or secondsubstituent is present at the 5 or 7 position.

In another embodiment, the compound of Formula (II), or apharmaceutically acceptable salt thereof, is that wherein:

the first and second substituent are independently alkoxy, aryloxy,hydroxy or a group represented by the formula (a), (c), (d), (e), or(f);

R₃ and R₄ are hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, orcycloalkylalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, alkoxycarbonylalkyl, aryl, arylalkyl,or cycloalkylalkyl.

In another embodiment, the compound of Formula (II), or apharmaceutically acceptable salt thereof, is that wherein:

the first and second substituent are independently alkoxy, aryloxy or agroup represented by the formula (a), (c), (d), (e), or (f);

R₃ and R₄ are hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, orcycloalkylalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl or cycloalkylalkyl.

5.4.3 Pharmaceutical Compositions Comprising a Compound of Formula (III)

The present invention also encompasses compositions comprising acompound of Formula (III), the compound of Formula (III) being definedabove, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or vehicle.

In one embodiment, the compound of Formula (III), or a pharmaceuticallyacceptable salt thereof, is that wherein the first or second substituentis present at the 5, 7, or 9 position. Preferably, the first or secondsubstituent is present at the 5 or 7 position.

In another embodiment, the compound of Formula (III), or apharmaceutically acceptable salt thereof, is that wherein:

the first and second substituent are independently alkoxy, aryloxy,hydroxy or a group represented by the formula (a), (c), (d), (e), or(f);

R₃ and R₄ are hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, orcycloalkylalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, alkoxycarbonylalkyl, aryl, arylalkyl,or cycloalkylalkyl.

In another embodiment, the compound of Formula (m), or apharmaceutically acceptable salt thereof, is that wherein:

the first and second substituent are independently alkoxy, aryloxy or agroup represented by the formula (a), (c), (d), (e), or (f);

R₃ and R₄ are hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, orcycloalkylalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl or cycloalkylalkyl.

5.4.4 Pharmaceutical Compositions Comprising a Compound of Formula (IV)

The present invention also encompasses compositions comprising acompound of Formula (IV), the compound of Formula (IV) being definedabove, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or vehicle.

In one embodiment the compound of Formula (IV), or a pharmaceuticallyacceptable salt thereof, is that wherein the first or second substituentis present at the 5 or 7 position.

In a second embodiment, the compound of Formula (IV), or apharmaceutically acceptable salt thereof, is that wherein the first andsecond substituent are independently alkyl, trifluoromethyl, sulfonyl,carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy,arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy,aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a grouprepresented by formula (a), (c), (d), (e), or (f).

In another embodiment, the compound of Formula (IV), or apharmaceutically acceptable salt thereof, is that wherein:

the first and second substituent are independently alkoxy, aryloxy,hydroxy or a group represented by the formula (a), (c), (d), (e), or(f);

R₃ and R₄ are hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, orcycloalkylalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, alkoxycarbonylalkyl, aryl, arylalkyl,or cycloalkylalkyl.

In another embodiment, the compound of Formula (IV), or apharmaceutically acceptable salt thereof, is that wherein:

the first and second substituent are independently alkoxy, aryloxy or agroup represented by the formula (a), (c), (d), (e), or (f);

R₃ and R₄ are hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, orcycloalkylalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl or cycloalkylalkyl.

5.4.5 Pharmaceutical Compositions Comprising a Compound of Formula (V)

The present invention also encompasses compositions comprising acompound of Formula (V), the compound of Formula (V) being definedabove, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or vehicle.

In one embodiment, the compound of Formula (V), or a pharmaceuticallyacceptable salt thereof, is that wherein the first or second substituentis present at the 5 or 7 position.

In another embodiment, the compound of Formula (V), or apharmaceutically acceptable salt thereof, is that wherein the compoundof Formula (V) is disubstituted and at least one of the substituents isa group represented by the formula (d) or (f).

5.4.6 Pharmaceutical Compositions Comprising a Compound of Formula (VI)

The present invention further provides pharmaceutical compositionscomprising:

(A) a compound having the formula:

or a pharmaceutically acceptable salt thereof,

wherein R₀ is —O—, —S—, —S(O)—, —S(O)₂— or —CH₂—;

the compound being (i) unsubstituted, (ii) monosubstituted and having afirst substituent, or (iii) disubstituted and having a first substituentand a second substituent;

the first or second substituent, when present, being at the 3, 4, 5, 7,8, 9, or 10 position, wherein the first and second substituent, whenpresent, are independently alkyl, halogen, hydroxy, nitro,trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl,aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy,alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy,di-alkylaminoalkoxy, or a group represented by formula (a), (b), (c),(d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino,di-alkylamino, arylamino, arylalkylamino, cycloalkylamino,cycloalkylalkylamino, aminoalkyl, mono-alkylaminioalkyl, ordi-alkylaminoalkyl; and

(B) a pharmaceutically acceptable carrier or vehicle.

In one embodiment, the first or second substituent of compounds ofFormula VI, when present, are at the 3, 4, 5, 7, 8, 9, or 10 position,wherein the first and second substituent, when present, areindependently alkyl, halogen, nitro, trifluoromethyl, sulfonyl,carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy,arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy,aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a grouprepresented by formula (a), (b), (c), (d), (e), (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, amino, mono-alkylamino, di-alkylamino, arylamino,arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl,mono-alkylaminioalkyl, or di-alkylaminoalkyl.

The present pharmaceutical compositions, which comprise a compound ofFormula (I)-(V) or (VI), or a pharmaceutically acceptable salt thereof,(collectively “the present compositions”) and a pharmaceuticallyacceptable carrier or vehicle, are useful for treating or preventing adisease associated with the modulation of JNK. Preferably, the presentcompositions are useful for inhibiting JNK. The present compositions arealso useful for treating cancer; rheumatoid arthritis; rheumatoidspondylitis; osteoarthritis; gout; asthma; bronchitis; cystic fibrosis;inflammatory bowel disease; irritable bowel syndrome; mucous colitis;ulcerative colitis; Crohn's disease; gastritis; esophagitis; hepatitis;multiple sclerosis; endotoxin shock; psoriasis; eczema; dermatitis;atherosclerosis; restenosis following angioplasty; left ventricularhypertrophy; myocardial infarction; stroke; ischemic damage to theheart, kidney, liver, or brain; transplant rejection; systemic lupuserythomatosus; pancreatitis; chronic obstructive pulmonary disease;conjunctive heart failure or a central or peripheral neurologicaldegenerative disorder.

5.5 Methods

The methods of the invention encompass treating or preventing a diseaseassociated with the modulation of JNK, comprising administering to apatient in need thereof an effective amount of a compound of Formulas(I)-(VI), the compound of Formula (VI) being defined above, or apharmaceutically acceptable salt thereof. The present invention alsoencompasses treating or preventing a disease, comprising administeringto a patient in need thereof an effective amount of a compound ofFormula (I)-(VI) or a pharmaceutically acceptable salt thereof, whereinthe disease is cancer; rheumatoid arthritis; rheumatoid spondylitis;osteoarthritis; gout; asthma; bronchitis; cystic fibrosis; inflammatorybowel disease; irritable bowel syndrome; mucous colitis; ulcerativecolitis; Crohn's disease; gastritis; esophagitis; hepatitis; multiplesclerosis; endotoxin shock; psoriasis; eczema; dermatitis;atherosclerosis; restenosis following angioplasty; left ventricularhypertrophy; myocardial infarction; stroke; ischemic damage to theheart, kidney, liver, or brain; transplant rejection; systemic lupuserythomatosus; pancreatitis; chronic obstructive pulmonary disease;conjunctive heart failure or a central or peripheral neurologicaldegenerative disorder.

5.5.1 Methods Comprising Administering a Compound of Formula (I)

The present methods of the invention also encompass administering to apatient in need thereof an effective amount of a compound of Formula(I), the compound of Formula (I) being defined above, or apharmaceutically acceptable salt thereof.

In one embodiment of the methods of the invention, the compound ofFormula (I), or a pharmaceutically acceptable salt thereof, is thatwherein the first or second substituent is present at the 5, 7, or 9position. Preferably, the first or second substituent is present at the5 or 7 position

In another embodiment of the methods of the invention, the compound ofFormula (I), or a pharmaceutically acceptable salt thereof, is thatwherein:

the first or second substituent is present at the 5, 7, or 9 position;

the first and second substituent are independently alkoxy, aryloxy,hydroxy or a group represented by the formula (a), (c), (d), (e), or(f);

R₃ and R₄ are independently hydrogen, alkyl, cycloalkyl, aryl,arylalkyl, or cycloalkylalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, alkoxycarbonylalkylor cycloalkylalkyl.

In another embodiment of the methods of the invention, the compound ofFormula (I), or a pharmaceutically acceptable salt thereof, is thatwherein:

the first or second substituent is present at the 5, 7, or 9 position;

the first and second substituent are independently alkoxy, aryloxy or agroup represented by the formula (a), (c), (d), (e), or (f);

R₃ and R₄ are independently hydrogen, alkyl, cycloalkyl, aryl,arylalkyl, or cycloalkylalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or cycloalkylalkyl.

5.5.2 Methods Comprising Administering a Compound of Formula (ID

The present methods of the invention also encompass administering to apatient in need thereof an effective amount of a compound of Formula(II), the compound of Formula (II) being defined above, or apharmaceutically acceptable salt thereof.

In one embodiment of the methods of the invention, the compound ofFormula (II), or a pharmaceutically acceptable salt thereof, is thatwherein the first or second substituent, when present, is present at the5, 7, or 9 position. Preferably, the first or second substituent ispresent at the 5 or 7 position

In another embodiment of the methods of the invention, the compound ofFormula (II), or a pharmaceutically acceptable salt thereof, is thatwherein:

the first and second substituent are independently alkoxy, aryloxy,hydroxy or a group represented by the formula (a), (c), (d), (e), or(f);

R₃ and R₄ are independently hydrogen, alkyl, cycloalkyl, aryl,arylalkyl, or cycloalkylalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, alkoxycarbonylalkylor cycloalkylalkyl.

In another embodiment of the methods of the invention, the compound ofFormula (II), or a pharmaceutically acceptable salt thereof, is thatwherein:

the first and second substituent are independently alkoxy, aryloxy or agroup represented by the formula (a), (c), (d), (e), or (f);

R₃ and R₄ are independently hydrogen, alkyl, cycloalkyl, aryl,arylalkyl, or cycloalkylalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl or cycloalkylalkyl.

5.5.3 Methods Comprising Administering a Compound of Formula (III)

The present methods of the invention also encompass administering to apatient in need thereof an effective amount of a compound of Formula(III), the compound of Formula (III) being defined above, or apharmaceutically acceptable salt thereof.

In one embodiment of the methods of the invention, the compound ofFormula (III), or a pharmaceutically acceptable salt thereof, is thatwherein the first or second substituent is present at the 5, 7, or 9position. Preferably, the first or second substituent is present at the5 or 7 position

In another embodiment of the methods of the invention, the compound ofFormula (III), or a pharmaceutically acceptable salt thereof, is thatwherein:

the first and second substituent are independently alkoxy, aryloxy,hydroxy or a group represented by the formula (a), (c), (d), (e), or(f);

R₃ and R₄ are independently hydrogen, alkyl, cycloalkyl, aryl,arylalkyl, or cycloalkylalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, alkoxycarbonylalkylor cycloalkylalkyl.

In another embodiment of the methods of the invention, the compound ofFormula (III), or a pharmaceutically acceptable salt thereof, is thatwherein:

the first and second substituent are independently alkoxy, aryloxy or agroup represented by the formula (a), (c), (d), (e), or (f);

R₃ and R₄ are independently hydrogen, alkyl, cycloalkyl, aryl,arylalkyl, or cycloalkylalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl or cycloalkylalkyl.

5.5.4 Method Comprising Administering a Compound of Formula (IV)

The present methods of the invention also encompass administering to apatient in need thereof an effective amount of a compound of Formula(IV), the compound of Formula (IV) being defined above, or apharmaceutically acceptable salt thereof.

In one embodiment of the methods of the invention, the compound ofFormula (IV), or a pharmaceutically acceptable salt thereof, is thatwherein the first or second substituent is present at the 5 or 7position

In a second embodiment of the methods of the invention, the compound ofFormula (IV), or a pharmaceutically acceptable salt thereof, is thatwherein the first and second substituent are independently alkyl,trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl,aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy,alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy,di-alkylaminoalkoxy, or a group represented by formula (a), (c), (d),(e), or (f).

In another embodiment of the methods of the invention, the compound ofFormula (IV), or a pharmaceutically acceptable salt thereof, is thatwherein:

the first and second substituent are independently alkoxy, aryloxy,hydroxy or a group represented by the formula (a), (c), (d), (e), or(f);

R₃ and R₄ are independently hydrogen, alkyl, cycloalkyl, aryl,arylalkyl, or cycloalkylalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, alkoxycarbonylalkylor cycloalkylalkyl.

In another embodiment of the methods of the invention, the compound ofFormula (IV), or a pharmaceutically acceptable salt thereof, is thatwherein:

the first and second substituent are independently alkoxy, aryloxy or agroup represented by the formula (a), (c), (d), (e), or (f);

R₃ and R₄ are independently hydrogen, alkyl, cycloalkyl, aryl,arylalkyl, or cycloalkylalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl or cycloalkylalkyl.

5.5.5 Methods Comprising Administering a Compound of Formula (V)

The present methods of the invention also encompass administering to apatient in need thereof an effective amount of a compound of Formula(V), the compound of Formula (V) being defined above, or apharmaceutically acceptable salt thereof.

In one embodiment of the methods of the invention, the compound ofFormula (V), or a pharmaceutically acceptable salt thereof, is thatwherein the first or second substituent is present at the 5 or 7position

In one embodiment of the methods of the invention, the compound ofFormula (V), or a pharmaceutically acceptable salt thereof, is thatwherein the compound of Formula (V) is disubstituted and at least one ofthe substituents is a group represented by the formula (d) or (f).

While the invention contemplates modulating all JNK, modulation of JNKwhich is expressed in the brain is important for treating central orperipheral neurological degenerative disorders like epilepsy,Alzheimer's disease, Parkinson's disease, Huntington's disease,amyotrophic laterial sclerosis, peripheral neuropathy, and spinal corddamage. Thus, in a preferred embodiment of the methods of the invention,the disease that is treated or prevented is a central or peripheralneurological degenerative disorder, wherein the central or peripheralneurological degenerative disorder is epilepsy, Alzheimer's disease,Parkinson's disease, Huntington's disease, amyotrophic laterialsclerosis, peripheral neuropathy, or spinal cord damage.

The methods of the invention are also useful for treating or preventingcancer; rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis;gout; asthma; bronchitis; cystic fibrosis; inflammatory bowel disease;irritable bowel syndrome; mucous colitis; ulcerative colitis; Crohn'sdisease; gastritis; esophagitis; hepatitis; multiple sclerosis;endotoxin shock; psoriasis; eczema; dermatitis; atherosclerosis;restenosis following angioplasty; left ventricular hypertrophy,myocardial infarction; stroke; ischemic damage to the heart, kidney,liver, or brain; transplant rejection; systemic lupus erythomatosus;pancreatitis; chronic obstructive pulmonary disease; conjunctive heartfailure or a central or peripheral neurological degenerative disorder.

Preferably, the compound of Formula (I)-(VI) is:

a compound of formula VII:

wherein A and B are:

A B Compound —NH₂ —NH₂ FK —N(CH₂CH₂CH₂CH₃)₂ —N(CH₂CH₂CH₂CH₃)₂ FL —NHC₆H₅—NHC₆H₅ FM —OC₆H₅ —OC₆H₅ FN —NH₂ —N(CH₂CH₂CH₂CH₃)₂ FO —NH₂—N(CH₂CH₂CN)(CH₂CH₂OH) FP —NH₂ —N(CH₂CH₂CH₂CH₃)₂ FQ —NHCH₃ —NHCH₃ FR—N(CH₃)₂ —N(CH₃)₂ FS —N(CH₂CH₃)₂ —N(CH₂CH₃)₂ FT —NHCH₂CH₃ —NHCH₂CH₃ FU—OCH₃ —OCH₃ FV —OCH₂CH₃ —OCH₂CH₃ FW —OCH₂CH₂OCH₃ —OCH₂CH₂OCH₃ FX

FY —Cl —Cl FZ —NHCH₂CH₂OH —NHCH₂CH₂OH GA —NHCH₂CH₂CH₂CH₃ —NHCH₂CH₂CH₂CH₃GB —F —OCH₂CH₂CH₂CH₃ GC —F —OCH(CH₃)₂ GD —F —OCH₂CH(CH₂CH₃)CH₂CH₂CH₂CH₃GE —F —OCH₂CH₂OC₆H₅ GF —F —OCH₂CH═CH₂ GG —F —OCH₂CHCN GH —F —O(CH₂)₃OCH₃GI —F —O(CH₂)₂O(CH₂)₂OCH₃ GJ —F —OCH₂C₆H₅ GK —F —OCH₂CH₂OH GL —F—OCH₂(4-chlorophenyl) GM —F —OCH₂CH₂Cl GN —F —OCH₂CH₂OCH₂CH₂CH₂CH₃ GO —F—O(CH₂)₅CH₃ GP —F

GQ —F

GR —F —OCH₂CH(OH)CH₂OCH₃ GS —F —OCH₂CH₂OC(O)C₆H₅ GT —F —OCH₂CH₂OCH₂C₆H₅GU —F —OCH₂C(O)OCH₂CH₂C═CH₂ GV —F —OCH₂CH₂OCH₃ GW —F —OCH₂CH₂C₆H₅ GX —F—OCH₃ GY —F —OCH₂CH₂OCH₂CH₂CN GZ —Cl —NHCH₂CH₂OCH₂CH₂OCH₂CH₂CH₂CH₃ HA—OCH₂CH₂CH₂CH₃ —NHCH₂CH₂OCH₂CH₂OCH₂CH₂CH₂CH₃ HB

HC

or a pharmaceutically acceptable salt thereof.

More preferably, the compound of Formula (VI) is Compound CC, or apharmaceutically acceptable salt thereof.

5.6 Therapeutic/Prophylactic Administration

When administered to a patient, e.g., an animal for veterinary use or toa human for clinical use, the compounds of Formula (I)-(VI), orpharmaceutically acceptable salts thereof, are preferably in isolatedform. By “isolated” it is meant that prior to administration, a compoundof Formula (I)-(VI), or a pharmaceutically acceptable salt thereof, isseparated from other components of a synthetic organic chemical reactionmixture or natural product source, e.g., plant matter, tissue culture,or bacterial broth. Preferably, the compounds of Formula (I)-(VI), orpharmaceutically acceptable salts thereof, are isolated via conventionaltechniques, e.g., extraction followed by chromatography,recrystalization, or another conventional technique. When in isolatedform, the compounds of Formula (I)-(VI), or pharmaceutically acceptablesalts thereof, are at least 90%, preferably at least 95%, of a compoundof Formula (I)-(VI), or a pharmaceutically acceptable salt thereof, byweight of that which is isolated. “Single compound of Formula (I)-(VI),or a pharmaceutically acceptable salt thereof,” as used herein, means acompound of Formula (I)-(VI) and racemates and/or enantiomers thereof,and pharmaceutically acceptable salts thereof.

The invention provides methods of treatment and prophylaxis byadministration to a patient of an effective amount of a compound ofFormula (I)-(VI), or a pharmaceutically acceptable salt thereof. Thepatient is preferably an animal, including, but not limited, to ananimal such as a cow, horse, sheep, pig, chicken, turkey, quail, cat,dog, mouse, rat, rabbit, or guinea pig and is more preferably a mammal,and most preferably a human.

The present pharmaceutical compositions, which comprise one or more ofthe compounds of Formula (I)-(VI), or pharmaceutically acceptable saltsthereof, can be administered by any convenient route, for example byinfusion or bolus injection, by absorption through epithelial ormucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa)and can be administered together with another biologically active agent.Administration can be systemic or local. Various delivery systems areknown, e.g., encapsulation in liposomes, microparticles, microcapsules,and capsules, and can be used to administer a compound of the invention.In certain embodiments, more than one compound of Formula (I)-(VI), or apharmaceutically acceptable salt thereof, is administered to a patient.Methods of administration include but are not limited to intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intranasal, intracerebral, intravaginal,transdermal, rectally, by inhalation, or topically to the ears, nose,eyes, or skin. The preferred mode of administration is left to thediscretion of the practitioner, and will depend in-part upon the medicalcondition and the site of the medical condition.

In specific embodiments, it might be desirable to administer one or moreof the compounds of Formula (I)-(VI), or a pharmaceutically acceptablesalt thereof, locally to the area in need of treatment. This can beachieved, for example, and not by way of limitation, by local infusionduring surgery, topical application, e.g., in conjunction with a wounddressing after surgery, by injection, by means of a catheter, by meansof a suppository, or by means of an implant, said implant being of aporous, non-porous, or gelatinous material, including membranes, such assialastic membranes, or fibers. In one embodiment, administration can beby direct injection at the site (or former site) of a cancer, tumor, orneoplastic or pre-neoplastic tissue.

In certain embodiments, it might be desirable to introduce one or moreof the compounds of Formula (I)-(VI), or a pharmaceutically acceptablesalt thereof, into the central nervous system by any suitable route,including intraventricular and intrathecal injection. Intraventricularinjection can be facilitated by an intraventricular catheter, forexample, attached to a reservoir, such as an Ommaya reservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the compounds of Formula (I)-(VI), orpharmaceutically acceptable salts thereof, can be formulated as asuppository, with traditional binders and carriers such astriglycerides.

In another embodiment, the compounds of Formula (I)-(VI), orpharmaceutically acceptable salts thereof, can be delivered in avesicle, in particular a liposome (see Langer, Science 249:1527-1533(1990); Treat et al., in Liposomes in the Therapy of Infectious Diseaseand Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp.353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generallyibid.).

In yet another embodiment, the compounds of Formula (I)-(VI), orpharmaceutically acceptable salts thereof, can be delivered in acontrolled release system. In one embodiment, a pump can be used (seeLanger, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987);Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med.321:574 (1989)). In another embodiment, polymeric materials can be used(see Medical Applications of Controlled Release, Langer and Wise (eds.),CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability,Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, NewYork (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem.23:61 (1983); see also Levy et al., Science 228:190 (1985); During etal., Ann. Neurol. 25:351 (1989); Howard et al., J. Neurosurg. 71:105(1989)). In yet another embodiment, a controlled-release system can beplaced in proximity of the target of the compound of the invention,e.g., the brain, thus, requiring only a fraction of the systemic dose(see, e.g., Goodson, in Medical Applications of Controlled Release,supra, vol. 2, pp. 115-138 (1984)). Other controlled-release systems arediscussed in the review by Langer (Science 249:1527-1533 (1990)) can beused.

The present pharmaceutical compositions will contain an effective amountof the compounds of Formula (I)-(VI), or pharmaceutically acceptablesalts thereof, preferably in purified form, together with a suitableamount of a pharmaceutically acceptable carrier so as to provide theform for proper administration to the patient.

In a specific embodiment, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of the Federal or a state government orlisted in the U.S. Pharmacopeia or other generally recognizedpharmacopeia for use in animals, and more particularly in humans. Theterm “carrier” refers to a diluent, adjuvant, excipient, or vehicle withwhich a compound of the invention is administered. Such pharmaceuticalcarriers can be liquids, such as water and oils, including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. The pharmaceuticalcarriers can be saline, gum acacia, gelatin, starch paste, talc,keratin, colloidal silica, urea, and the like. In addition, auxiliary,stabilizing, thickening, lubricating, and coloring agents can be used.When administered to a patient, the pharmaceutically acceptable carriersare preferably sterile. When the pharmaceutically acceptable carrier iswater or an aqueous base the water or aqueous base is sterile. Water isa preferred carrier when the compounds of Formula (I)-(VI), orpharmaceutically acceptable salts thereof, are administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid carriers, particularly forinjectable solutions. Suitable pharmaceutical carriers also includeexcipients such as starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,water, ethanol, and the like. The present pharmaceutical compositions,if desired, can also contain minor amounts of wetting or emulsifyingagents, or pH buffering agents.

The present pharmaceutical compositions can take the form of solutions,suspensions, emulsion, tablets, pills, pellets, capsules, capsulescontaining liquids, powders, sustained-release formulations,suppositories, emulsions, aerosols, sprays, suspensions, or any otherform suitable for use. In one embodiment, the pharmaceuticallyacceptable carrier is a capsule (see e.g., U.S. Pat. No. 5,698,155).Other examples of suitable pharmaceutical carriers are described in“Remington's Pharmaceutical Sciences” by E. W. Martin.

In a preferred embodiment, the compounds of Formula (I)-(VI), orpharmaceutically acceptable salts thereof, are formulated in accordancewith routine procedures as a pharmaceutical composition adapted forintravenous administration to human beings. Typically, the compounds ofFormula (I)-(VI), or pharmaceutically acceptable salts thereof, forintravenous administration are solutions in sterile isotonic aqueousbuffer. Where necessary, the compositions can also include asolubilizing agent. Compositions for intravenous administration canoptionally include a local anesthetic such as lignocaine to ease pain atthe site of the injection. Generally, the ingredients are suppliedeither separately or mixed together in unit dosage form, for example, asa dry lyophilized powder or water free concentrate in a hermeticallysealed container such as an ampoule or sachette indicating the quantityof active agent. Where the compounds of Formula (I)-(VI), orpharmaceutically acceptable salts thereof, are to be administered byinfusion, they can be dispensed, for example, with an infusion bottlecontaining sterile pharmaceutical grade water or saline. Where thecompounds of Formula (I)-(VI), or pharmaceutically acceptable saltsthereof, are administered by injection, an ampule of sterile water forinjection or saline can be provided so that the ingredients can be mixedprior to administration.

Compositions for oral delivery can be in the form of tablets, lozenges,aqueous or oily suspensions, granules, powders, emulsions, capsules,syrups, or elixirs, for example. Orally administered compositions cancontain one or more optional agents, for example, sweetening agents suchas fructose, aspartame or saccharin; flavoring agents such aspeppermint, oil of wintergreen, or cherry; coloring agents; andpreserving agents, to provide a pharmaceutically palatable preparation.Moreover, where in tablet or pill form, the compositions can be coatedto delay disintegration and absorption in the gastrointestinal tractthereby providing a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administering the presentcompounds. In these later platforms, fluid from the environmentsurrounding the capsule is imbibed by the driving compound, which swellsto displace the agent or agent composition through an aperture. Thesedelivery platforms can provide an essentially zero order deliveryprofile as opposed to the spiked profiles of immediate releaseformulations. A time delay material such as glycerol monostearate orglycerol stearate can also be used. Oral compositions can includestandard carriers such as mannitol, lactose, starch, magnesium stearate,sodium saccharine, cellulose, and magnesium carbonate.

The amount of the compound of Formula (I)-(VI), or a pharmaceuticallyacceptable salt thereof, that will be effective in the treatment of aparticular disorder or condition will depend on the nature of thedisorder or condition, and can be determined by standard clinicaltechniques. In addition, in vitro or in vivo assays can optionally beemployed to help identify optimal dosage ranges. The precise dose to beemployed in the compositions will also depend on the route ofadministration, and the seriousness of the disease or disorder, andshould be decided according to the judgment of the practitioner and eachpatient's circumstances. However, suitable dosage ranges are generallyabout 0.1 milligrams to about 250 milligrams, preferably, about 1 mg toabout 100 mg and, more preferably, about 5 mg to about 50 mg. whereineach dose can be given 1 to 6 times a day, preferably 1 to 4 times perday. Effective doses can be extrapolated from dose-response curvesderived from in vitro or animal model test systems. Such animal modelsand systems are well known in the art.

The invention also provides pharmaceutical packs or kits comprising oneor more containers filled with one or more of the present compounds.Optionally associated with such container(s) can be a notice in the formprescribed by a governmental agency regulating the manufacture, use, orsale of pharmaceuticals or biological products, which notice reflectsapproval by the agency of manufacture for use or sale for humanadministration.

The present compounds of Formula (I)-(VI), or pharmaceuticallyacceptable salts thereof, are preferably assayed in vitro, and then invivo, for the desired therapeutic or prophylactic activity, prior to usein humans. For example, in vitro assays can be used to determine whetheradministration of a specific compound or combination of the compounds ofFormula (I)-(VI), or pharmaceutically acceptable salts thereof, ispreferred. The compounds of Formula (I)-(VI), or pharmaceuticallyacceptable salts thereof, can also be demonstrated effective and safeusing animal model systems.

5.7 EXAMPLES 5.7.1 Example Synthesis of Compound CC

To a suspension of 3.0 g of 1-aminoanthraquinone in 45 mL of DMSO wasadded 9 g of ammonium thiocyanate. The reaction mixture was then heatedto 50° C. and 15 mL of sulfuric acid added dropwise (exothermicreaction). The reaction mixture was then allowed to stir at roomtemperature for 16 hours. After stirring, 300 mL of water were added tothe reaction mixture and the resulting suspension was filtered and driedin a vacuum oven to provide a crude product. The above procedure wasthen repeated using the crude product in place of 1-aminoanthraquinone.The resulting crude thiocyanate-addition intermediate was thenrecrystallized with o-dichlorobenzene (total volume 250 mL) to provide1.9 g of a thiocyanate-addition intermediate. The structure of thethiocyanate-addition intermediate was confirmed by ¹H NMR andelectrospray mass spectrometry. ¹H NMR (DMSO-d₆): 8.19 (dd, 1H), 8.14(dd, 1H), 7.93 (dt, 1H), 7.86 (dt, 1H), 7.81 (d, 1H), 7.43 (d, 1H).ES-MS (m/z) 281 [M+1]⁺.

A suspension of 300 mg of the thiocyanate-addition intermediate in 25 mLof liquid ammonia was heated to 140° C. in a bomb for 5 hours, thereaction mixture was diluted with 300 mL of water, and the reactionmixture was filtered to provide a final crude product. The final crudeproduct was then purified using preparative HPLC (5 cm YMC C-18 columnoperated at a flow rate of 60 ml/min with a gradient elution from 40%aqueous acetonitrile with 0.1% trifluoroacetic acid to 100% acetonitrilewith 0.1% trifluoroacetic acid over 20 minutes) to provide 55 mg ofCompound CC. The structure of Compound CC was confirmed by ¹H NMR andelectrospray mass spectrometry. ¹H NMR (DMSO-d₆): 8.49 (d, 1H), 8.39 (d,1H), 8.29 (d, 1H), 7.89 (t, 1H), 7.78 (t, 1H), 7.28 (d, 1H). ES-MS (m/z)253 [M+1]⁺.

5.7.2 Example Synthesis of Compound HD

A solution of compound CC in water/sulfuric acid was heated to 180° C.overnight to give the named compound. ¹H NMR (DMSO-d₆): 8.23 (d, 2H),7.91 (pent, 2H), 7.76 (d, 1H), 7.22 (d, 1H). ES-MS (m/z) 254 [M+1]⁺.

5.7.3 Example Synthesis of Compound CH

To a solution of compound CC (30 mg, 0.012 mmol) in pyridine (5 mL) wasadded acetyl chloride (10 μL, 0.14 mmol). After stirring at roomtemperature overnight, water was added and the product recovered byfiltration (28 mg). ¹H NMR (DMSO-d₆): 11.95 (s, 1H), 8.95 (d, 1H), 8.55(d, 1H), 8.38 (d, 1H), 8.26 (d, 1H), 7.91 (t, 1H), 7.77 (t, 1H), 2.30(s, 3H). ES-MS (m/z) 295 [M+1]⁺.

5.7.4 Example Synthesis of Compound HE

Compound HE was prepared according to the methodology of compound CH. ¹HNMR (DMSO-d₆): 13.1 (s, 1H), 9.23 (d, 1H), 8.71 (d, 1H), 8.48 (d, 1H),8.42 (d, 1H), 8.13 (d, 2H), 7.96 (t, 1H), 7.82 (t, 1H), 7.72 (m, 3H).ES-MS (m/z) 357 [M+1]⁺.

5.7.5 Example Synthesis of Compound HF

Compound HF was prepared according to the methodology of compound CH. ¹HNMR (DMSO-d₆): 12.1 (s, 1H), 8.97 (d, 1H), 8.60 (d, 1H), 8.43 (d, 1H),8.34 (d, 1H), 7.94 (t, 1H), 7.80 (t, 1H), 3.62 (s, 3H), 2.90 (t, 2H),2.71 (t, 2H). ES-MS (m/z) 367 [M+1]⁺.

5.7.6 Example Synthesis of Compound HG

Compound HG was prepared according to the methodology of compound CH. ¹HNMR (DMSO-d₆): 13.1 (s, 1H), 9.29 (s, 1H), 9.18 (d, 1H), 8.90 (d, 1H),8.73 (d, 1H), 8.45 (m, 3H), 7.97 (t, 1H), 7.82 (t, 1H), 7.74 (m, 1H).ES-MS (m/z) 357 [M+1]⁺.

5.7.7 Example Biological Activity of Compound CC

JNK Assay:

To 10 μL of Compound (CC) in 20% DMSO/80% dilution buffer containing of20 mM HEPES (pH 7.6), 0.1 mM EDTA, 2.5 mM magnesium chloride, 0.004%Triton×100, 2 μg/mL leupeptin, 20 mM β-glycerolphosphate, 0.1 mM sodiumvanadate, and 2 mM DTT in water was added 30 μL of 50-200 ng His6-JNK1,JNK2, or JNK3 in the same dilution buffer. The mixture was pre-incubatedfor 30 minutes at room temperature. Sixty microliter of 10 μgGST-c-Jun(1-79) in assay buffer consisting of 20 mM HEPES (pH 7.6), 50mM sodium chloride, 0.1 mM EDTA, 24 mM magnesium chloride, 1 mM DTT, 25mM PNPP, 0.05% Triton×100, 11 μM ATP, and 0.5 μCi γ-32P ATP in water wasadded and the reaction was allowed to proceed for 1 hour at roomtemperature. The c-Jun phosphorylation was terminated by addition of 150μL of 12.5% trichloroacetic acid. After 30 minutes, the precipitate washarvested onto a filter plate, diluted with 50 μL of the scintillationfluid and quantified by a counter. The IC₅₀ values were calculated asthe concentration of Compound (CC) at which the c-Jun phosphorylationwas reduced to 50% of the control value. Compounds that inhibit JNKpreferably have an IC₅₀ value ranging 0.01-10 μM in this assay. Compound(CC) has an IC₅₀ according to this assay of 1 μM for JNK2 and 400 nM forJNK3. The measured IC₅₀ value for Compound CC, as measured by the aboveassay, however, shows some variability due to the limited solubility ofCompound CC in aqueous media. Despite the variability, however, theassay consistently does show that Compound CC inhibits JNK. This assaydemonstrates that Compound (CC), illustrative of the present compounds,inhibits JNK2 and JNK3 and, accordingly, is useful for treating orpreventing a disorder alleviated by modulating JNK, preferably byinhibiting JNK.

Selectivity for JNK:

Compound (CC) was also assayed for its inhibitory activity againstseveral protein kinases, listed below, using techniques known to thoseskilled in art (See, e.g., Protein Phosphorylation, Sefton & Hunter,Eds., Academic Press, pp. 97-367, 1998). The following IC₅₀ values wereobtained:

Enzyme IC₅₀ p38-2 >30,000 nM MEK6 >30,000 nM LKK1 >30,000 nMIKK2 >30,000 nM

This assay shows that Compound (CC), illustrative of the presentcompounds, selectively inhibits JNK relative to other protein kinasesand, accordingly, is a selective JNK inhibitor. Therefore, Compound (CC)is useful for selectively treating or preventing a disorder alleviatedby modulating JNK, preferably by inhibiting JNK.

Jurkat T-Cell IL-2 Production Assay:

Jurkat T cells (clone E6-1) were purchased from the American TypeCulture Collection of Manassas, Va. and maintained in growth mediaconsisting of RPMI 1640 medium containing 2 mM L-glutamine (commerciallyavailable from Mediatech Inc. of Herndon, Va.), with 10% fetal bovineserum (commercially available from Hyclone Laboratories Inc. of Omaha,Nebr.) and penicillin/streptomycin. All cells were cultured at 37° C. in95% air and 5% CO₂. Cells were plated at a density of 0.2×10⁶ cells perwell in 200 μL of media. Compound stock (20 mM) was diluted in growthmedia and added to each well as a 10× concentrated solution in a volumeof 25 μL, mixed, and allowed to pre-incubate with cells for 30 minutes.The compound vehicle (dimethylsulfoxide) was maintained at a finalconcentration of 0.5% in all samples. After 30 minutes the cells wereactivated with PMA (phorbol myristate acetate, final concentration 50ng/mL) and PHA (phytohemagglutinin, final concentration 2 μg/mL). PMAand PHA were added as a 10× concentrated solution made up in growthmedia and added in a volume of 25 μL per well. Cell plates were culturedfor 10 hours. Cells were pelleted by centrifugation and the mediaremoved and stored at −20° C. Media aliquots are analyzed by sandwichELISA for the presence of IL-2 as per the manufacturers instructions(Endogen Inc. of Woburn, Mass.). The IC₅₀ values were calculated as theconcentration of Compound (CC) at which the IL-2 production was reducedto 50% of the control value. Compounds that inhibit JNK preferably havean IC₅₀ value ranging from 0.1-30 μM in this assay. Compound (CC) has anIC₅₀ of 30 μM. The measured IC₅₀ value for Compound CC, as measured bythe above assay, however, shows some variability due to the limitedsolubility of Compound CC in aqueous media. Despite the variability,however, the assay consistently does show that Compound CC inhibits JNK.

This assay shows that Compound (CC), illustrative of the presentcompound, inhibits IL-2 production in Jurkat T-cells and accordinglyinhibits JNK. Therefore, Compound (CC) is useful for selectivelytreating or preventing a disorder alleviated by modulating JNK,preferably by inhibiting JNK.

[³H]Dopamine Cell Culture Assay:

Cultures of dopaminergic neurons were prepared according to amodification of the procedure described by Raymon and Leslie (J.Neurochem. 62, 1015-1024, 1994). Time-mated pregnant rats weresacrificed on embyronic day 14-15 (crown rump length 11-12 mm) and theembryos removed by cesarean section. The ventral mesencephalon,containing the dopaminergic neurons, was dissected from each embryo.Tissue pieces from approximately 48 embryos were pooled and dissociatedboth enzymatically and mechanically. An aliquot from the resulting cellsuspension was counted and the cells were plated in high glucoseDMEM/F12 culture medium with 10% fetal bovine serum at a density of1×10⁵ cells/well of a Biocoat poly-D-lysine-coated 96-well plate. Theday following plating was considered 1 day in vitro (DIV). Cells weremaintained in a stable environment at 37° C., 95% humidity, and 5% CO₂.A partial medium change was performed at 3 DIV. At 7 DIV, cells weretreated with the neurotoxin, 6-hydroxydopamine (6-OHDA, 30 μM) in thepresence and absence of Compound CC. Cultures were processed for[³H]dopamine uptake 22 hours later.

[³H]Dopamine uptake is used as a measure of the health and integrity ofdopaminergic neurons in culture (Prochiantz et al., PNAS 76: 5387-5391,1979). It was used in these studies to monitor the viability ofdopaminergic neurons following exposure to the neurotoxin 6-OHDA. 6-OHDAhas been shown to damage dopaminergic neurons both in vitro and in vivoand is used to model the cell death observed in Parkinson's disease(Ungerstedt, U., Eur. J. Pharm., 5 (1968) 107-110 and Hefti et al.,Brain Res., 195 (1980) 123-137). Briefly, cells treated with 6-OHDA inthe presence and absence of Compound CC were assessed in the uptakeassay 22 hrs after exposure to 6-OHDA. Culture medium was removed andreplaced with warm phosphate buffered saline (PBS) with calcium andmagnesium, 10 μM pargyline, 1 mM ascorbic acid, and 50 nM [³H]dopamine.Cultures were incubated at 37° C. for 20 min. Radioactivity was removedand the cultures were washed 3× with ice cold PBS. To determine theintracellular accumulation of [³H]dopamine, cells were lysed with M-PERdetergent and an aliquot was taken for liquid scintillation counting.The measured effect of Compound CC on the intracellular accumulation of[³H]dopamine, as measured by the above assay, however, shows somevariability due to the limited solubility of Compound CC in aqueousmedia. Despite the variability, however, the assay consistently doesshow that Compound CC protects rat ventral mesencephalan neurons fromthe toxic effects of 6-OHDA

As shown in FIG. 1, Compound CC, at a concentration of approximately3×10⁻⁶ M, protects rat ventral mesencephalan neurons from the toxiceffects of 6-OHDA. Despite the variability discussed above, the assayconsistently does show that Compound CC protects rat ventralmesencephalan neurons from the toxic effects of 6-OHDA Accordingly,Compound CC, illustrative of the present compounds, is useful fortreating or preventing Parkinson's disease.

5.7.8 Example Brain-Blood Plasma Distribution of Compound CC In Vivo

Compound CC was administered intravenously (10 mg/kg) into the veins ofSprague-Dawley rats. After 2 hr, blood samples were obtained from theanimals and their vascular systems were perfused with approximately 100mL of saline to rid their brains of blood. The brains were removed fromthe animals, weighed, and homogenized in a 50 mL conical tube containing10 equivalents (w/v) of methanol/saline (1:1) using a Tissue Tearer(Fischer Scientific). The homogenized material was extracted by adding600 μL of cold methanol to 250 μL of brain homogenate vortexed for 30sec and subjected to centrifugation for 5 min. After centrifugation, 600μL of the resulting supernatant was transferred to a clean tube andevaporated at room temperature under reduced pressure to provide apellet. The resulting pellet was reconstituted in 250 μL of 30% aqueousmethanol to provide a brain homogenate analysis sample. A plasmaanalysis sample was obtained using the brain homogenate analysis sampleprocedure described above by substituting plasma for brain homogenate.Standard plasma samples and standard brain homogenate samples containingknown amounts of Compound CC were also prepared by adding 5 μL of serialdilutions (50:1) of a solution of Compound CC freshly prepared in coldethanol to 250 μL of control rat plasma (Bioreclamation of Hicksville,N.Y.) or control brain homogenate. The standard plasma samples andstandard brain homogenate samples were then subjected to the sameextraction by protein precipitation, centrifugation, evaporation, andreconstitution procedure used for the brain homogenate to provide brainhomogenate standard analysis samples and plasma standard analysissamples. The brain homogenate analysis samples, plasma analysis samples,and standard analysis samples were analyzed and compared using HPLC byinjecting 100 μL of a sample onto a 5 μm C-18 Luna column (4.6 mm×150mm, commercially available from Phenomenex of Torrance, Calif.) andeluting at 1 mL/min with a linear gradient of 30% aqueous acetonitrilecontaining 0.1% trifluoroacetic acid to 90% aqueous acetonitrilecontaining 0.1% trifluoroacetic acid over 8 minutes and holding at 90%aqueous acetonitrile containing 0.1% trifluoroacetic acid for 3 min.with absorbance detection at 450 nm. Recovery of Compound CC was 56±5.7%for plasma and 42±6.2% for the brain. The concentration of Compound CCin the brain and plasma was determined by comparing HPLC chromatogramsobtained from the brain homogenate analysis samples and plasma analysissamples to standard curves constructed from analysis of the brainhomogenate standard analysis samples and the plasma standard analysissamples, respectively. Results from this study show that Compound CC,following intravenous administration, crosses the blood-brain barrier toa significant extent. In particular, brain-drug concentrations wereapproximately 65 nmole/g and plasma concentrations were approximately 7μM at 2 hr post-dose, resulting in a brain-plasma concentration ratio ofapproximately 9-fold (assuming 1 g of brain tissue is equivalent to 1 mLof plasma). This example shows that Compound CC, illustrative of thepresent compounds, has enhanced ability to cross the blood-brainbarrier. In addition, this example shows that the present compounds, inparticular Compound CC, when administered to a patient can cross theblood-brain barrier.

It will be appreciated that, although specific embodiments of theinvention have been described herein for purposes of illustration, theinvention described and claimed herein is not to be limited in scope bythe specific embodiments herein disclosed. These embodiments areintended as illustrations of several aspects of the invention. Anyequivalent embodiments are intended to be within the scope of thisinvention. Indeed, various modifications of the invention in addition tothose shown and described herein will become apparent to those skilledin the art from the foregoing description. Such modifications are alsointended to fall within the scope of the appended claims.

A number of references have been cited, the entire disclosure of whichare incorporated herein by reference.

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, being (i) unsubstituted,(ii) monosubstituted and having a first substituent, or (iii)disubstituted and having a first substituent and a second substituent;the first or second substituent, when present, being at the 3, 4, 5, 7,8, 9, or 10 position; the first and second substituent, when present,are independently alkyl, halogen, nitro, trifluoromethyl, sulfonyl,alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl,cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy,aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a grouprepresented by formula (a), (b), (c), (d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and R₅ is hydrogen, alkyl, cycloalkyl, aryl,arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, amino, mono-alkylamino,di-alkylamino, arylamino, arylalkylamino, cycloalkylamino,cycloalkylalkylamino, aminoalkyl, mono-alkylaminioalkyl, ordi-alkylaminoalkyl.
 2. The compound of claim 1, wherein the first orsecond substituent are present at the 5, 7, or 9 position.
 3. Thecompound of claim 2, wherein the first and second substituent areindependently alkoxy, aryloxy, aminoalkyl, mono-alkylaminoalkyl,di-alkylaminoalkyl, or a group represented by the formula (a), (c), (d),(e), or (f); R₃ and R₄ are independently hydrogen, alkyl, cycloalkyl,aryl, arylalkyl, or cycloalkylalkyl; and R₅ is hydrogen, alkyl,cycloalkyl, aryl, arylalkyl, alkoxycarbonyl or cycloalkylalkyl.
 4. Apharmaceutical composition comprising a compound, or a pharmaceuticallyacceptable salt of the compound, having the formula:

or a pharmaceutically acceptable salt thereof, being (i) unsubstituted,(ii) monosubstituted and having a first substituent, or (iii)disubstituted and having a first substituent and a second substituent;the first or second substituent, when present, being at the 3, 4, 5, 7,8, 9, or 10 position; the first and second substituent, when present,are independently alkyl, halogen, nitro, trifluoromethyl, sulfonyl,carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy,arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy,aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a grouprepresented by formula (a), (b), (c), (d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and R₅ is hydrogen, alkyl, cycloalkyl, aryl,arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, amino, mono-alkylamino,di-alkylamino, arylamino, arylalkylamino, cycloalkylamino,cycloalkylalkylamino, aminoalkyl, mono-alkylaminioalkyl, ordi-alkylaminoalkyl; and a pharmaceutically acceptable carrier orvehicle.